Proteasome inhibitors and methods of using the same

ABSTRACT

The present invention provides boronic acid compounds, boronic esters, and compositions thereof that can modulate apoptosis such as by inhibition of proteasome activity. The compounds and compositions can be used in methods of inducing apoptosis and treating diseases such as cancer and other disorders associated directly of indirectly with proteasome activity.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/020,425, filed Feb. 3, 2011 (now U.S. Pat. No. 8,058,262, issued Nov.15, 2011), which is a continuation of U.S. application Ser. No.12/496,359, filed Jul. 1, 2009 (now U.S. Pat. No. 7,915,236, issued Mar.29, 2011), which is a divisional of U.S. application Ser. No.10/918,664, filed Aug. 12, 2004 (now U.S. Pat. No. 7,576,206, issuedAug. 18, 2009), which claims the benefit of U.S. Provisional ApplicationNo. 60/495,764, filed Aug. 14, 2003, the disclosures of which areincorporated herein by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates to boronic acid and boronic estercompounds useful as proteasome inhibitors and modulation of apoptosis.

BACKGROUND OF THE INVENTION

The proteasome, (also referred to as multicatalytic protease (MCP),multicatalytic proteinase, multicatalytic proteinase complex,multicatalytic endopeptidase complex, 20S, 26S, or ingensin) is a large,multiprotein complex present in both the cytoplasm and the nucleus ofall eukaryotic cells. It is a highly conserved cellular structure thatis responsible for the ATP-dependent proteolysis of most cellularproteins (Tanaka, Biochem Biophy. Res. Commun., 1998, 247, 537). The 26Sproteasome consists of a 20S core catalytic complex that is capped ateach end by a 19S regulatory subunit. The archaebacterial 20S proteasomecontains fourteen copies of two distinct types of subunits, α and β,which form a cylindrical structure consisting of four stacked rings. Thetop and bottom rings contain seven α-subunits each, while the innerrings contain seven β-subunits. The more complex eukaryotic 20Sproteasome is composed of about 15 distinct 20-30 kDa subunits and ischaracterized by three major activities with respect to peptidesubstrates. For example, the proteasome displays tryptic-,chymotryptic-, and peptidylglutamyl peptide-hydrolytic activities(Rivett, Biochem. J., 1993, 291, 1 and Orlowski, Biochemistry, 1990, 29,10289). Further, the proteasome has a unique active site mechanism whichis believed to utilize a threonine residue as the catalytic nucleophile(Seemuller, et al., Science, 1995, 268, 579).

The 26S proteasome is able to degrade proteins that have been marked bythe addition of ubiquitin molecules. Typically, ubiquitin is attached tothe ε-amino groups of lysines in a multistep process utilizing ATP andE1 (ubiquitin activating) and E2 (ubiquitin-conjugating) enzymes.Multi-ubiquitinated substrate proteins are recognized by the 26Sproteasome and are degraded. The multi-ubiquitin chains are generallyreleased from the complex and ubiquitin is recycled (Goldberg, et al.,Nature, 1992, 357, 375).

Numerous regulatory proteins are substrates for ubiquitin dependentproteolysis. Many of these proteins function as regulators ofphysiological as well as pathophysiological cellular processes.Alterations in proteasome activity have been implicated in a number ofpathologies including neurodegenerative diseases such as Parkinson'sdisease, Alzheimer's disease, as well as occlusion/ischaemia reperfusioninjuries, and aging of the central nervous system.

The ubiquitin-proteasome pathway also plays a role in neoplastic growth.The regulated degradation of proteins such as cyclins, CDK2 inhibitors,and tumor suppressors is believed to be important in cell cycleprogression and mitosis. A known substrate of the proteasome is thetumor suppressor p53 which is involved in several cellular processes(see, e.g., Ko, L. J. Genes Dev., 1996, 10, 1054). Tumor suppressor p53has been shown to induce apoptosis in several haematopoietic cell lines(Oren, M., Semin. Cancer Biol., 1994, 5, 221). Induction of p53 leads tocell growth arrest in the G1 phase of the cell cycle as well as celldeath by apoptosis. Tumor suppressor p53 degradation is known to becarried out via the ubiquitin-proteasome pathway, and disrupting p53degradation by inhibition of the proteasome is a possible mode ofinducing apoptosis.

The proteasome is also required for activation of the transcriptionfactor NF-κB by degradation of its inhibitory protein, IκB (Palombella,et al., Cell, 1994, 78, 773). NF-κB has a role in maintaining cellviability through the transcription of inhibitors of apoptosis. Blockadeof NF-κB activity has been demonstrated to make cells more susceptibleto apoptosis.

Several inhibitors of the proteolytic activity of the proteasome havebeen reported. See, for example, Kisselev, et al., Chemistry & Biology,2001, 8, 739. Lactacystin is a Streptomyces metabolite that specificallyinhibits the proteolytic activity of the proteasome complex (Fenteany,et al., Science, 1995, 268, 726). This molecule is capable of inhibitingthe proliferation of several cell types (Fenteany, et al., Proc. Natl.Acad. Sci. USA, 1994, 91, 3358). It has been shown that lactacystinbinds irreversibly, through its β-lactone moiety, to a threonine residuelocated at the amino terminus of the β-subunit of the proteasome.

Peptide aldehydes have been reported to inhibit the chymotrypsin-likeactivity associated with the proteasome (Vinitsky, et al., Biochemistry,1992, 31, 9421; Tsubuki, et al., Biochem. Biophys. Res. Commun., 1993,196, 1195; and Rock, et al., Cell, 1994, 78, 761). Dipeptidyl aldehydeinhibitors that have IC₅₀ values in the 10-100 nM range in vitro (Iqbal,M., et al., J. Med. Chem., 1995, 38, 2276) have also been reported. Aseries of similarly potent in vitro inhibitors from α.-ketocarbonyl andboronic ester derived dipeptides has also been reported (Iqbal, et al.,Bioorg. Med. Chem. Lett., 1996, 6, 287, U.S. Pat. Nos. 5,614,649;5,830,870; 5,990,083; 6,096,778; 6,310,057; U.S. Pat. App. Pub. No.2001/0012854, and WO 99/30707).

N-terminal peptidyl boronic ester and acid compounds have been reportedpreviously (U.S. Pat. Nos. 4,499,082 and 4,537,773; WO 91/13904;Kettner, et al., J. Biol. Chem., 1984, 259(24), 15106). These compoundsare reported to be inhibitors of certain proteolytic enzymes. N-terminaltri-peptide boronic ester and acid compounds have been shown to inhibitthe growth of cancer cells (U.S. Pat. No. 5,106,948). A broad class ofN-terminal tri-peptide boronic ester and acid compounds and analogsthereof has been shown to inhibit renin (U.S. Pat. No. 5,169,841).

Various inhibitors of the peptidase activities of the proteasome havealso been reported. See, e.g., Dick, et al., Biochemistry, 1991, 30,2725; Goldberg, et al., Nature, 1992, 357, 375; Goldberg, Eur. J.Biochem., 1992, 203, 9; Orlowski, Biochemistry, 1990, 29, 10289; Rivett,et al., Archs. Biochem. Biophys., 1989, 218, 1; Rivett, et al., J. Biol.Chem., 1989, 264, 12215; Tanaka, et al., New Biol., 1992, 4, 1;Murakami, et al., Proc. Natl. Acad. Sci. USA, 1986, 83, 7588; Li et al.,Biochemistry, 1991, 30, 9709; Goldberg, Eur. J. Biochem., 1992, 203, 9;and Aoyagi, et al., Proteases and Biological Control, Cold Spring HarborLaboratory Press (1975), pp. 429-454.

Stein et al., U.S. patent application Ser. No. 08/212,909, filed Mar.15, 1994, report peptide aldehydes useful for reducing in an animal boththe rate of loss of muscle mass and the rate of intracellular proteinbreakdown. The compounds are also said to reduce the rate of degradationof p53 protein in an animal. Palombella, et al., WO 95/25533, report theuse of peptide aldehydes to reduce the cellular content and activity ofNF-κB in an animal by contacting cells of the animal with a peptidealdehyde inhibitor of proteasome function or ubiquitin conjugation.Goldberg and Rock, WO 94/17816, report the use of proteasome inhibitorsto inhibit MHC-I antigen presentation. Stein, et al., U.S. Pat. No.5,693,617 report peptidyl aldehyde compounds as proteasome inhibitorsuseful for reducing the rate of degradation of protein in an animalInhibition of the 26S and 20S proteasome by indanone derivatives and amethod for inhibiting cell proliferation using indanone derivatives arereported by Lum et al., U.S. Pat. No. 5,834,487. Alpha-ketoamidecompounds useful for treating disorders mediated by 20S proteasome inmammals are reported in Wang et al., U.S. Pat. No. 6,075,150. France, etal., WO 00/64863, report the use of 2,4-diamino-3-hydroxycarboxylic acidderivatives as proteasome inhibitors. Carboxylic acid derivatives asproteasome inhibitors are reported by Yamaguchi et al., EP 1166781.Ditzel, et al., EP 0 995 757 report bivalent inhibitors of theproteasome. 2-Aminobenzylstatine derivatives that inhibit non-covalentlythe chymotrypsin-like activity of the 20S proteasome have been reportedby Garcia-Echeverria, et al., Bioorg. Med. Chem. Lett., 2001, 11, 1317.

Some further proteasome inhibitors can contain boron moieties. Forexample, Drexler et al., WO 00/64467, report a method of selectivelyinducing apoptosis in activated endothelial cells or leukemic cellshaving a high expression level of c-myc by using tetrapeptidic boronatecontaining proteasome inhibitors. Furet et al., WO 02/096933 report2-[[N-(2-amino-3-(heteroaryl oraryl)propionyl)aminoacyl]amino]alkylboronic acids and esters for thetherapeutic treatment of proliferative diseases in warm-blooded animals.U.S. Pat. Nos. 6,083,903; 6,297,217; 5,780,454; 6,066,730; 6,297,217;6,548,668; U.S. Patent Application Pub. No. 2002/0173488; and WO96/13266 report boronic ester and acid compounds and a method forreducing the rate of degradation of proteins. A method for inhibitingviral replication using certain boronic acids and esters is alsoreported in U.S. Pat. No. 6,465,433 and WO 01/02424. Pharmaceuticallyacceptable compositions of boronic acids and novel boronic acidanhydrides and boronate ester compounds are reported by Plamondon, etal., U.S. Patent Application Pub. No. 2002/0188100. A series of di- andtripeptidyl boronic acids are shown to be inhibitors of 20S and 26Sproteasome in Gardner, et al., Biochem. J., 2000, 346, 447.

Other boron-containing peptidyl and related compounds are reported inU.S. Pat. Nos. 5,250,720; 5,242,904; 5,187,157; 5,159,060; 5,106,948;4,963,655; 4,499,082; and WO 89/09225, WO/98/17679, WO 98/22496, WO00/66557, WO 02/059130, WO 03/15706, WO 96/12499, WO 95/20603, WO95/09838, WO 94/25051, WO 94/25049, WO 94/04653, WO 02/08187, EP 632026,and EP 354522.

A great interest exists, as evidenced by the above references, in drugswhich can modulate proteasome activity. For example, molecules capableof inhibiting proteasome activity can arrest or delay cancer progressionby interfering with the ordered degradation of cell cycle proteins ortumor suppressors. Accordingly, there is an ongoing need for new and/orimproved inhibitors of proteasome.

SUMMARY OF THE INVENTION

The present invention is directed to novel boronic acid and boronicester compounds useful as proteasome inhibitors and modulation ofapoptosis. The subject invention also comprises methods for inhibitionof multicatalytic protease (“MCP”) associated with certain disorders,including the treatment of muscle wasting disorders.

In one embodiment are provided compounds having Formula (I):

wherein constituent members are defined infra, as well as preferredconstituent members.

In another embodiment the present invention provides a pharmaceuticalcomposition comprising a compound of Formula (I) and a pharmaceuticallyacceptable carrier.

In another embodiment the present invention provides a method ofinhibiting activity of proteasome comprising contacting a compound ofFormula (I) with said proteasome.

In another embodiment the present invention provides a method oftreating cancer comprising administering to a mammal having orpredisposed to said cancer a therapeutically effective amount of acompound of Formula (I).

In another embodiment the present invention provides a method oftreating cancer treating cancer comprising administering to a mammalhaving or predisposed to said cancer a therapeutically effective amountof a compound of Formula (I), and wherein said cancer is selected fromskin, prostate, colorectal, pancreas, kidney, ovary, mammary, liver,tongue, lung, and smooth muscle tissue.

In another embodiment the present invention provides a method oftreating cancer comprising administering to a mammal having orpredisposed to said cancer a therapeutically effective amount of acompound of Formula (I), and wherein said cancer is selected fromleukemia, lymphoma, non-Hodgkin lymphoma, myeloma, and multiple myeloma.

In another embodiment the present invention provides a method oftreating cancer comprising administering to a mammal having orpredisposed to said cancer a therapeutically effective amount of acompound of Formula (I) in combination with one or more antitumor oranticancer agent and/or radiotherapy.

In another embodiment the present invention provides a method ofinhibiting activity of transcription factor NF-κB comprising contactingIκB, the inhibitor of transcription factor NF-κB, with a compound ofFormula (I).

In another embodiment, the present invention provides processes forpreparing a compound of Formula (II):

wherein constituent members are defined herein, by reacting a diol ofFormula (II-b):

with an appropriate trialkoxyborane of Formula (II-a):

wherein constituent members are defined herein; for a time and underconditions suitable for forming an intermediate of Formula (II-c):

and reacting the intermediate of Formula (II-c) with either i) a reagentof formula R¹CH₂MX^(hal), wherein M is a metal and X^(hal) is a halogenatom, or ii) a reagent of formula R¹CH₂Li, for a time and underconditions suitable for forming the compound of Formula (II).

These and other features of the compounds will be set forth in expandedform as the disclosure continues.

DESCRIPTION OF EMBODIMENTS OF THE INVENTION

The present invention provides, inter alia, compounds that can inhibitproteasome activity and be used for the treatment of diseases ordisorders related to proteasome activity. Compounds of the inventioninclude compounds of Formula (I)

or pharmaceutically acceptable salt, stereoisomeric or tautomeric formthereof, wherein:

-   R¹ is C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, or C₃-C₇    cycloalkyl;-   R² is H, —(CH₂)_(a)CH₂NHC(═NR⁴)NH—Y, —(CH₂)_(b)CH₂CONR⁵R⁶,    —(CH₂)_(c)CH₂N(R⁴)CONH₂, —(CH₂)_(d)CH(R⁷)NR⁹R¹⁰, or    —(CH₂)_(e)CH(R⁷)ZR⁸;-   a, b, and c are each, independently, 0, 1, 2, 3, 4, 5, or 6;-   d and e are each, independently, 0, 1, 2, 3, or 4;-   R⁴ is H or C₁-C₁₀ alkyl;-   R⁵ and R⁶ are each, independently, H, C₁-C₁₀ alkyl, carbocyclyl,    heterocarbocyclyl, or an amino protecting group;-   alternatively, R⁵ and R⁶ together with the N atom to which they are    attached form a heterocarbocyclyl group;-   R⁷ is H or C₁-C₁₀ alkyl;-   R⁸ is H, C₁-C₁₀ alkyl, alkyl-S(═O)₂—, aryl-S(═O)₂—, H₂NS(═O)₂—,    —SO₃H, or a protecting group;-   R⁹ is H, C₁-C₁₀ alkyl, carbocyclyl, or heterocarbocyclyl;-   R¹⁰ is H, C₁-C₁₀ alkyl, carbocyclyl, heterocarbocyclyl, C₁-C₁₀    alkyl-C(═O)—, C₂-C₁₀ alkenyl-C(═O)—, C₂-C₁₀ alkynyl-C(═O)—,    carbocyclyl-C(═O)—, heterocarbocyclyl-C(═O)—,    carbocyclylalkyl-C(═O)—, heterocarbocyclylalkyl-C(═O)—, C₁-C₁₀    alkyl-S(═O)₂—, carbocyclyl-S(═O)₂—, heterocarbocyclyl-S(═O)₂—,    carbocyclylalkyl-S(═O)₂—, heterocarbocyclylalkyl-S(═O)₂—, C₁-C₁₀    alkyl-NHC(═O)—, carbocyclyl-NHC(═O)—, heterocarbocyclyl-NHC(═O)—,    carbocyclylalkyl-NHC(═O)—, heterocarbocyclylalkyl-NHC(═O)—, C₁-C₁₀    alkyl-OC(═O)—, carbocyclyl-OC(═O)—, heterocarbocyclyl-OC(═O)—,    carbocyclylalkyl-OC(═O)—, heterocarbocyclylalkyl-OC(═O)—, C₁-C₁₀    alkyl-NH—C(═O)—NHS(═O)₂—, carbocyclyl-NH—C(═O)—NHS(═O)₂—,    heterocarbocyclyl-NH—C(═O)—NHS(═O)₂—, C₁-C₁₀ alkyl-S(═O)₂—NH—C(═O)—,    carbocyclyl-S(═O)₂—NH—C(═O)—, heterocarbocyclyl-S(═O)₂—NH—C(═O)—, or    an amino protecting group; wherein R¹⁰ is optionally substituted    with 1, 2 or 3, R²³;-   alternatively, R⁹ and R¹⁰ together with the N atom to which they are    attached form a heterocarbocyclyl group optionally substituted with    1, 2 or 3 R²³;-   Y is H, —CN, —NO₂, —S(═O)₂R¹¹, or a guanidino protecting group;-   R¹¹ is C₁-C₆ alkyl, aryl, or NR¹²R¹³;-   R¹² and R¹³ are, independently, H, C₁-C₁₀ alkyl, carbocyclyl,    heterocarbocyclyl, or an amino protecting group;    -   alternatively, R¹² and R¹³ together with the N atom to which        they are attached form a heterocarbocyclyl group;-   Z is O, S, Se, or Te;-   Q is —B(OH)₂, —B(OR¹⁴)₂, or a cyclic boronic ester wherein said    cyclic boronic ester contains from 2 to 20 carbon atoms, and,    optionally, a heteroatom which can be N, S, or O;-   R¹⁴ is H, C₁-C₄ alkyl, cycloalkyl, cycloalkylalkyl, aryl, or    aralkyl;-   X is R^(A)C(═O)—, R^(A)NHC(═O)—, R^(A)S(═O)₂—, R^(A)C(═O)—,    R^(A)SC(═O)—, or R^(A);-   R^(A) is C₁-C₂₀ alkyl optionally substituted with R²⁰; C₂-C₂₀    alkenyl optionally substituted with R²⁰; C₂-C₂₀ alkynyl optionally    substituted with R²⁰; carbocyclyl optionally substituted with 1-5    R²¹; or heterocarbocyclyl optionally substituted with 1-5 R²¹;-   R²⁰ is selected from the group consisting of:    -   —CN, halo, haloalkyl-, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄        alkynyl, —CO₂H, —C(═O)CO₂H, —C(═O)NH₂, —C(═O)H, —S(═O)NH₂,        —S(═O)₂NH₂, —OH, —SH, —NH₂, —NH(alkyl), —N(alkyl)₂, —NHC(═O)NH₂,        —NHC(═O)R^(20a), —NHC(═O)OR^(20a), —OR^(20a), —SR^(20a),        —S(═O)R^(20a), —S(═O)₂R^(20a), —S(═O)₂—NHR^(20a),        —SC(═O)R^(20a), —C(═O)R^(20a), —C(═O)NHR^(20a), —C(═O)O—R^(20a),        —NHS(═O)₂R^(20a), —NHR^(20b), phthalimido, —(O-alkyl)_(r)-OH,        —(O-alkyl)_(r)-(O-alkyl), —OR^(20c), —SR^(20c),        —O-alkyl-R^(20c), —S-alkyl-R^(20c), —S(═O)—R^(20c),        —S(═O)₂—R^(20c), —S(═O)₂—NHR^(20c), —SC(═O)R^(20c),        —C(═O)OR^(20c), —C(═O)NHR^(20c), carbocyclyl optionally        substituted with 1-5 R²¹; and heterocarbocyclyl optionally        substituted with 1-5 R²¹;-   R^(20a) is C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, or C₂-C₂₀ alkynyl; wherein    said alkyl, alkenyl, or alkynyl is optionally substituted by one or    more halo, OH, CN, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₂-C₈ alkoxyalkoxy,    aryl, heteroaryl or —NHR^(20b);-   R^(20b) is an amino protecting group;-   R^(20c) is carbocyclyl optionally substituted with 1-5 R²²; or    heterocarbocyclyl optionally substituted with 1-5 R²²;-   R²¹ is selected from the group consisting of:    -   C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, —OR^(21a),        SR^(21a), —CN, halo, haloalkyl, —NH₂, —NH(alkyl), —N(alkyl)₂,        —NHC(═O)O-alkyl, —NHC(═O)alkyl, —COOH, —C(═O)O-alkyl,        —C(═O)alkyl, —C(O)H, —S(═O)-alkyl, —S(═O)₂-alkyl, —S(═O)-aryl,        —S(═O)₂-aryl, carbocyclyl optionally substituted with 1-5 R²²,        and heterocarbocyclyl optionally substituted with 1-5 R²²;-   R^(21a) is H, C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl,    carbocyclyl or heterocarbocyclyl;-   R²² is selected from the group consisting of:    -   C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, phenyl, halo,        haloalkyl, alkoxy, thialkoxy, amino, alkylamino, dialkylamino,        carboxyl, alkyl-OC(═O)—, alkyl-C(═O)—, aryl-OC(═O)—,        alkyl-OC(═O)NH—, aryl-OC(═O)NH—, alkyl-C(═O)NH—, alkyl-C(═O)O—,        (alkyl-O)_(r)-alkyl, HO-(alkyl-O)_(r)-alkyl-, —OH, —SH, —CN,        —N₃, —CNO, —CNS, alkyl-S(═O)—, alkyl-S(═O)₂—, H₂NS(═O)—, and        H₂NS(═O)₂—;-   R²³ is selected from the group consisting of:    -   C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, F, Cl, Br, I,        haloalkyl, —NH₂, —NHR^(23a), —N(R^(23a))₂, —N₃, —NO₂, —CN, —CNO,        —CNS, —C(═O)OR^(23a), —C(═O)R^(23a), —OC(═O)R^(23a),        —N(R^(23a))C(═O)R^(23a), —N(R^(23a))C(═O)OR^(23a),        —C(═O)N(R^(23a))₂, ureido, —OR^(23a), —SR^(23a), —S(═O)—(C₁-C₆        alkyl), —S(═O)₂—(C₁-C₆ alkyl), —S(═O)-aryl, —S(═O)₂-aryl,        —S(═O)₂—N(R^(23a))₂; carbocyclyl optionally substituted with 1-5        R²⁴; and heterocarbocyclyl optionally substituted with 1-5 R²⁴;-   R^(23a) is H or C₁-C₆ alkyl;-   alternatively, two R^(23a) may be combined, together with the N atom    to which they are attached, to form a 5 to 7 membered heterocyclic    group; and-   R²⁴ is selected from the group consisting of:    -   C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, phenyl, halo,        haloalkyl, alkoxy, thialkoxy, amino, alkylamino, dialkylamino,        carboxyl, alkyl-OC(═O)—, alkyl-C(═O)—, aryl-OC(═O)—,        alkyl-OC(═O)NH—, aryl-OC(═O)NH—, alkyl-C(═O)NH—, alkyl-C(═O)O—,        (alkyl-O)_(r)-alkyl, HO-(alkyl-O)_(r)-alkyl-, —OH, —SH, —CN,        —N₃, —CNO, —CNS, alkyl-S(═O)—, alkyl-S(═O)₂—, H₂NS(═O)—, and        H₂NS(═O)₂—; and-   r is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;-   with the proviso that when Q is a 1,1,2,2-tetramethylethanediol    boronic ester, then X is not aralkyloxycarbonyl;-   with the proviso that when Q is a 1,1,2,2-tetramethylethanediol    boronic ester, and R¹ is cycloalkyl, then R² is not —CH₂CONH₂; and-   with the proviso that when X is R^(A)C(═O)—, R^(A) is a C₄-C₁₅    straight-chained alkyl substituted with R²⁰, and R²⁰ is —CN, —CO₂H,    —C(═O)O—R^(20a), —NHS(═O)₂R^(20a), —NHC(═O)R^(20a), —NHR^(20b), or    phthalimido; then R² is not —(CH₂)_(a)CH₂NHC(═NR⁴)NH—Y, wherein Y is    H, —CN, —NO₂, or a guanidino protecting group.

In further embodiments, when R² is —(CH₂)_(e)CH(R⁷)ZR⁸, e is 0, R⁷ is H,R⁸ is C₁-C₁₀ alkyl and X is R^(A)C(═O)—, then R^(A) is not aminoalkyl-,alkylaminoalkyl-, dialkylaminoalkyl-, or ureidoalkyl-.

In some embodiments, R¹ can be C₁-C₄ alkyl, and in further embodiments,R¹ can be propyl, such as 2-propyl.

In some embodiments, R² can be —(CH₂)_(a)CH₂NHC(═NR⁴)NH—Y,—(CH₂)_(b)CH₂CONR⁵R⁶, —(CH₂)_(c)CH₂N(R⁴)CONH₂, —(CH₂)_(d)CH(R⁷)NR⁹R¹⁰,or —(CH₂)_(e)CH(R⁷)ZR⁸.

In some embodiments, R² is —(CH₂)_(a)CH₂NHC(═NR⁴)NH—Y and a is 1, 2, 3,4, or 5.

In some embodiments, R² is —(CH₂)_(a)CH₂NHC(═NR⁴)NH—Y and a is 2.

In some embodiments, R² is —CH₂CH₂CH₂NHC(═NR⁴)NH—Y.

In some embodiments, R² is —(CH₂)_(d)CH(R⁷)NR⁹R¹⁰ and d is 0, 1, or 2.

In some embodiments, R² is —(CH₂)_(d)CH(R⁷)NR⁹R¹⁰ and d is 0.

In some embodiments, R² is —(CH₂)_(d)CH(R⁷)NR⁹R¹⁰ and R⁹ is H.

In some embodiments, R² is —(CH₂)_(d)CH(R⁷)NR⁹R¹⁰.

In some embodiments, R² is —CH(R⁷)NR⁹R¹⁰.

In some embodiments, R² is —CH₂NH—C(═O)OCH₂(C₆H₅).

In some embodiments, R² is —(CH₂)_(e)CH(R⁷)ZR⁸ and e is 0, 1, or 2.

In some embodiments, R² is —(CH₂)_(e)CH(R⁷)ZR⁸ and e is 0.

In some embodiments, R² is —(CH₂)_(e)CH(R⁷)ZR⁸.

In some embodiments, R² is —CH(R⁷)ZR⁸.

In further embodiments, Z is O.

In further embodiments, Q has Formula (II-a):

wherein D, R^(15a), R^(15b), R^(15c), R^(15d), p and q are definedherein below.

In further embodiments, Q is B(OH)₂ or a cyclic boronic ester whereinsaid cyclic boronic ester contains from 6 to 10 carbon atoms andcontains at least one cycloalkyl moiety.

In further embodiments Q is B(OH)₂.

In further embodiments Q is pinanediol boronic ester.

In further embodiments Q is bicyclohexyl-1,1′-diol boronic ester.

In further embodiments, Q is 1,2-dicyclohexyl-ethane-1,2-diol boronicester.

Alternatively, in some embodiments, Q is —B(OH)₂, —B(OR¹⁴)₂,

wherein:

R¹⁴, R^(15a), R^(15b), R^(15c), R^(15d), W, W¹, p and q are as definedhereinbelow.

In further embodiments Q is:

W is a substituted or unsubstituted C₄-C₁₀ cycloalkyl ring.

In some embodiments, X is R^(A)C(═O)—.

In some embodiments, X is R^(A)NHC(═O)—.

In some embodiments, X is R^(A)S(O)₂—.

In some embodiments, R^(A) is C₁-C₁₄ alkyl substituted by—(O-alkyl)_(r)-OH or

—(O-alkyl)_(r)-(O-alkyl), wherein r is 1, 2, 3, 4, or 5.

In some embodiments, R^(A) is C₁-C₁₄ alkyl substituted by—(O-alkyl)_(r)-OH or

—(O-alkyl)_(r)-(O-alkyl), wherein r is 1, 2 or 3.

In some embodiments, R^(A) comprises at least one —CH₂CH₂O— group.

In some embodiments, R^(A) is —CH₂(OCH₂CH₂)_(r)OCH₃.

In some embodiments, R^(A) is —CH₂OCH₂CH₂OCH₂CH₂OCH₃ or —CH₂OCH₂CH₂OCH₃.

In some embodiments, R^(A) is aryl or heteroaryl each optionallysubstituted with 1-5 R²¹.

In some embodiments, R^(A) is cycloalkyl or heterocycloalkyl eachoptionally substituted with 1-5 R²¹.

In some embodiments, R^(A) is C₁-C₂₀ alkyl; C₂-C₂₀ alkenyl; or C₂-C₂₀alkynyl, each optionally substituted with R²⁰.

In some embodiments, R^(A) is C₁-C₂₀ alkyl; C₂-C₂₀ alkenyl; or C₂-C₂₀alkynyl, each substituted with a carbocyclyl group or aheterocarbocyclyl group wherein said carbocyclyl group orheterocarbocyclyl group is optionally substituted with 1, 2 or 3 R²¹.

In some embodiments, R^(A) is C₁-C₂₀ alkyl; C₂-C₂₀ alkenyl; or C₂-C₂₀alkynyl, each substituted with an aryl group wherein said aryl group isoptionally substituted with 1, 2 or 3 R²¹.

In some embodiments, R^(A) is C₁-C₂₀ alkyl; C₂-C₂₀ alkenyl; or C₂-C₂₀alkynyl, each substituted with an heteroaryl group wherein saidheteroaryl group is optionally substituted with 1, 2 or 3 R²¹.

In some embodiments, R^(A) is C₁-C₂₀ alkyl; C₂-C₂₀ alkenyl; or C₂-C₂₀alkynyl, each substituted with an cycloalkyl group wherein saidcycloalkyl group is optionally substituted with 1, 2 or 3 R²¹.

In some embodiments, R^(A) is C₁-C₂₀ alkyl; C₂-C₂₀ alkenyl; or C₂-C₂₀alkynyl, each substituted with an heterocycloalkyl group wherein saidheterocycloalkyl group is optionally substituted with 1, 2 or 3 R²¹.

In some embodiments, R^(A) is C₁-C₂₀ alkyl; C₂-C₂₀ alkenyl; or C₂-C₂₀alkynyl, each optionally substituted with R²⁰, wherein R²⁰ is selectedfrom CN, halo, haloalkyl, —CO₂H, —C(═O)CO₂H, —C(═O)NH₂, —C(═O)H,—S(O)NH₂, —S(O)₂NH₂, —OH, —SH, —NH₂, —NH(alkyl), —N(alkyl)₂,—NHC(═O)NH₂, —NHC(═O)R^(20a), —NHC(═O)OR^(20a), —OR^(20a), —SR^(20a),—S(O)R^(20a), —S(O)₂R^(20a), —S(O)₂—NHR^(20a), —SC(═O)R^(20a),—C(═O)R^(20a), —C(═O)NHR^(20a), —C(═O)O—R^(20a), —NHS(O)₂R^(20a),—NHR^(20b), phthalimido, —(O-alkyl), —(O-alkyl)_(r)-OH,—(O-alkyl)_(r)-(O-alkyl), —OR^(20c), —SR^(20c), —O-alkyl-R^(20c),—S-alkyl-R^(20c), —S(O)—R^(20c), —S(O)₂—R^(20c), —S(O)₂—NHR^(20c),—SC(═O)R^(20e), —C(═O)R^(20c), —C(═O)OR^(20c), and —C(═O)NHR^(20c).

In some embodiments, R² is H and X is (O-alkyl)-(O-alkyl)_(r)-(C₁-C₁₄alkyl)-C(═O)— or HO-(alkyl-O)_(r)—(C₁-C₁₄ alkyl)-C(═O)—.

In some embodiments X is R^(A)C(═O)— and R^(A) is C₄-C₁₆ alkyl.

In some embodiments X is R^(A)C(═O)— and R^(A) is aryl optionallysubstituted with 1-3 R²¹.

In some embodiments X is R^(A)C(═O)— and R^(A) is heterocarbocyclylgroup optionally substituted with 1-3 R²¹.

In some embodiments X is R^(A)C(═O)—; R^(A) is phenyl substituted withone R²¹; and R²¹ is phenoxy.

In some embodiments X is R^(A)C(═O)—, R^(A) is C₁-C₄ alkyl substitutedwith R²⁰, and R²⁰ is aryl optionally substituted with 1-3 R²¹; and inyet further embodiments aryl is substituted by at least one halo.

In some embodiments X is R^(A)C(═O)—; R^(A) is C₁-C₁₄ alkyl substitutedwith R²⁰; and R²⁰ is —OR^(20a) or —OR^(20c).

In some embodiments X is R^(A)C(═O)—; R^(A) is C₁-C₁₄ alkyl substitutedwith R²⁰; and R²⁰ is heterocarbocyclyl optionally substituted with 1-3R²¹.

In some embodiments X is R^(A)S(O)₂— and R^(A) is C₃-C₁₆ alkyl.

In some embodiments the present invention provides compounds of Formula(I) wherein the stereochemistry is of Formula (I-s):

or pharmaceutically acceptable salt form thereof

In some embodiments, the present invention provides compounds of Formula(I)

or pharmaceutically acceptable salt, stereoisomeric or tautomeric formthereof, wherein:

-   R¹ is C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, or C₃-C₇    cycloalkyl;-   R² is H, —(CH₂)_(a)CH₂NHC(═NR⁴)NH—Y, —(CH₂)_(b)CH₂CONR⁵R⁶,    —(CH₂)_(c)CH₂N(R⁴)CONH₂, —(CH₂)_(d)CH(R⁷)NR⁹R¹⁰, or    —(CH₂)_(e)CH(R⁷)ZR⁸;-   a, b, and c are each, independently, 0, 1, 2, 3, 4, 5, or 6;-   d and e are each, independently, 0, 1, 2, 3, or 4;-   R⁴ is H or C₁-C₁₀ alkyl;-   R⁵ and R⁶ are each, independently, H, C₁-C₁₀ alkyl, carbocyclyl,    heterocarbocyclyl, or an amino protecting group;-   alternatively, R⁵ and R⁶ together with the N atom to which they are    attached form a heterocarbocyclyl group;-   R⁷ is H or C₁-C₁₀ alkyl;-   R⁸ is H, C₁-C₁₀ alkyl, alkyl-S(═O)₂—, aryl-S(═O)₂—, H₂NS(═O)₂—,    —SO₃H, or a protecting group;-   R⁹ is H, C₁-C₁₀ alkyl, carbocyclyl, or heterocarbocyclyl;-   R¹⁰ is H, C₁-C₁₀ alkyl, carbocyclyl, heterocarbocyclyl, C₁-C₁₀    alkyl-C(═O)—, carbocyclyl-C(═O)—, heterocarbocyclyl-C(═O)—,    carbocyclylalkyl-C(═O)—, heterocarbocyclylalkyl-C(═O)—, C₁-C₁₀    alkyl-S(═O)₂—, carbocyclyl-S(═O)₂—, heterocarbocyclyl-S(═O)₂—,    carbocyclylalkyl-S(═O)₂—, heterocarbocyclylalkyl-S(═O)₂—, C₁-C₁₀    alkyl-NHC(═O)—, carbocyclyl-NHC(═O)—, heterocarbocyclyl-NHC(═O)—,    carbocyclylalkyl-NHC(═O)—, heterocarbocyclylalkyl-NHC(═O)—, C₁-C₁₀    alkyl-OC(═O)—, carbocyclyl-OC(═O)—, heterocarbocyclyl-OC(═O)—,    carbocyclylalkyl-OC(═O)—, heterocarbocyclylalkyl-OC(═O)—, or an    amino protecting group; wherein R¹⁰ is optionally substituted with    1, 2, or 3 R²³;-   alternatively, R⁹ and R¹⁰ together with the N atom to which they are    attached form a heterocarbocyclyl group;-   Y is —H, —CN, —NO₂, —S(═O)₂R¹¹, or a guanidino protecting group;-   R¹¹ is C₁-C₆ alkyl, aryl, or NR¹²R¹³;-   R¹² and R¹³ are, independently, H, C₁-C₁₀ alkyl, carbocyclyl,    heterocarbocyclyl, or an amino protecting group;-   alternatively, R¹² and R¹³ together with the N atom to which they    are attached form a heterocarbocyclyl group;-   Z is O, S, Se, or Te;-   Q is —B(OH)₂, —B(OR¹⁴)₂, or a cyclic boronic ester wherein said    cyclic boronic ester contains from 2 to 20 carbon atoms, and,    optionally, a heteroatom which can be N, S, or O;-   R¹⁴ is H, C₁-C₄ alkyl, cycloalkyl, cycloalkylalkyl, aryl, or    aralkyl;-   X is R^(A)C(═O)—, R^(A)NHC(═O)—, R^(A)S(═O)₂—, R^(A)C(═O)—,    R^(A)SC(═O)—, or R^(A);-   R^(A) is C₁-C₂₀ alkyl optionally substituted with R²⁰; C₂-C₂₀    alkenyl optionally substituted with R²⁰; C₂-C₂₀ alkynyl optionally    substituted with R²⁰; carbocyclyl optionally substituted with 1-5    R²¹; or heterocarbocyclyl optionally substituted with 1-5 R²¹;-   R²⁰ is selected from the group consisting of:    -   —CN, halo, haloalkyl-, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄        alkynyl, —CO₂H, —C(═O)CO₂H, —C(═O)NH₂, —C(═O)H, —S(═O)NH₂,        —S(═O)₂NH₂, —OH, —SH, —NH₂, —NH(alkyl), —N(alkyl)₂, —NHC(═O)NH₂,        —NHC(═O)R^(20a), —NHC(═O)OR^(20a), —OR^(20a), —SR^(20a),        —S(═O)R^(20a), —S(═O)₂R^(20a), —S(═O)₂—NHR^(20a),        —SC(═O)R^(20a), —C(═O)R^(20a), —C(═O)NHR^(20a), —C(═O)O—R^(20a),        —NHS(═O)₂R^(20a), —NHR^(20b), phthalimido, —(—O-alkyl)_(r),        —O-alkyl-OH, —(O-alkyl)_(r)-OH, —OR^(20c), —SR^(20c),        —O-alkyl-R^(20c), —S-alkyl-R^(20c), —S(═O)—R^(20c),        —S(═O)₂—R^(20c), —S(═O)₂—NHR^(20c), —SC(═O)R^(20c),        —C(═O)R^(20c), —C(═O)OR^(20c), —C(═O)NHR^(20c), carbocyclyl        optionally substituted with 1-5 R²¹; and heterocarbocyclyl        optionally substituted with 1-5 R²¹;-   R^(20a) is C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, or C₂-C₂₀ alkynyl; wherein    said alkyl, alkenyl, or alkynyl is optionally substituted by one or    more halo, C₁-C₄ alkyl, aryl, heteroaryl or —NHR^(20b);-   R^(20b) is an amino protecting group;-   R^(20c) is carbocyclyl optionally substituted with 1-5 R²²; or    heterocarbocyclyl optionally substituted with 1-5 R²²;-   R²¹ is selected from the group consisting of:    -   C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, C₁-C₂₀ alkoxy,        C₁-C₂₀ thialkoxy, —OH, —CN, halo, haloalkyl, —NH₂, —NH(alkyl),        —N(alkyl)₂, —NHC(═O)O-alkyl, —NHC(═O)alkyl, —C(═O)O-alkyl,        —C(═O)alkyl, —S(═O)-alkyl, —S(═O)₂-alkyl, —S(═O)-aryl,        —S(═O)₂-aryl, carbocyclyl optionally substituted with 1-5 R²²;        and heterocarbocyclyl optionally substituted with 1-5 R²²;-   R²² is selected from the group consisting of:    -   C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, phenyl, halo,        haloalkyl, alkoxy, thialkoxy, amino, alkylamino, dialkylamino,        carboxyl, alkyl-OC(═O)—, alkyl-C(═O)—, aryl-OC(═O)—,        alkyl-OC(═O)NH—, aryl-OC(═O)NH—, alkyl-C(═O)NH—, alkyl-C(═O)O—,        (alkyl-O)_(r)-alkyl, HO-(alkyl-O)_(r)-alkyl-, —OH, —SH, —CN,        —N₃, —CNO, —CNS, alkyl-S(═O)—, alkyl-S(═O)₂—, H₂NS(═O)—, and        H₂NS(═O)₂—;-   R²³ is selected from the group consisting of:    -   C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, F, Cl, Br, I,        haloalkyl, —NH₂, —NHR^(23a), —N(R^(23a))₂, —N₃, —NO₂, —CN, —CNO,        —CNS, —C(═)OR^(23a), —C(═O)R^(23a), —OC(═O)R^(23a),        —N(R^(23a))C(═O)R^(23a), —C(═O)N(R^(23a))₂, ureido, —OR^(23a),        —SR^(23a), —S(═O)₂—(C₁-C₆ alkyl), —S(═O)₂-aryl, and        —S(═O)₂—N(R^(23a))₂;-   R^(23a) is H or C₁-C₆ alkyl;-   alternatively, two R^(23a) may be combined, together with the N atom    to which they are attached, to form a 5 to 7 membered heterocyclic    group; and-   r is 2, 3, 4, 5, 6, 7, 8, 9, or 10; and-   with the proviso that when Q is a 1,1,2,2-tetramethylethanediol    boronic ester, then X is not aralkyloxycarbonyl;-   with the proviso that when Q is a 1,1,2,2-tetramethylethanediol    boronic ester, and R¹ is cycloalkyl, then R² is not —CH₂CONH₂; and-   with the proviso that when X is R^(A)C(═O)—, R^(A) is a C₄-C₁₅    straight-chained alkyl substituted with R²⁰, and R²⁰ is —CN, —CO₂H,    —C(═O)O—R^(20a), —NHS(═O)₂R^(20a), —NHC(═O)R^(20a), —NHR^(20b), or    phthalimido; then R² is not —(CH₂)_(a)CH₂NHC(═NR⁴)NH—Y, wherein Y is    H, —CN, —NO₂, or a guanidino protecting group.

In some embodiments, R¹ is 2-propyl; R² is H,—(CH₂)_(a)CH₂NHC(═NR⁴)NH—Y, —(CH₂)_(b)CH₂CONR⁵R⁶,—(CH₂)_(c)CH₂N(R⁴)CONH₂, —(CH₂)_(d)CH(R⁷)NR⁹R¹⁰, or —(CH₂)_(e)CH(R⁷)ZR⁸;Q is —B(OH)₂ or pinanediol boronic ester; X is R^(A)C(═O)—; and R^(A) isC₄-C₁₆ alkyl; aryl optionally substituted with 1-3 R²¹; orheterocarbocyclyl group optionally substituted with 1-3 R²¹.

In some embodiments, the present invention provides compounds of Formula(I)

or pharmaceutically acceptable salt, stereoisomeric or tautomeric formthereof, wherein:

-   R¹ is C₁-C₈ alkyl;-   R² is —(CH₂)_(a)CH₂NHC(═NH)NH—Y, —(CH₂)_(c)CH₂NHCONH₂,    —(CH₂)_(d)CH(R⁷)NR⁹R¹⁰, or —(CH₂)_(e)CH(R⁷)ZR⁸;-   a is 1, 2, 3, 4, or 5;-   c is 1, 2, 3, 4, or 5;-   d is 0, 1, or 2;-   e is 0, 1, or 2;-   R⁷ is H or methyl;-   R⁸ is H, C₁-C₁₀ alkyl, —S(═O)₂-alkyl, —S(═O)₂-aryl, —S(═O)₂—NH₂,    —SO₃H, or a protecting group;-   Y is —H, —CN, —NO₂, —S(═O)₂R¹¹, or a guanidino protecting group;-   R⁹ is H, C₁-C₁₀ alkyl, carbocyclyl, or heterocarbocyclyl;-   R¹⁰ is H, C₁-C₁₀ alkyl, carbocyclyl, heterocarbocyclyl, C₁-C₁₀    alkyl-C(═O)—, carbocyclyl-C(═O)—, heterocarbocyclyl-C(═O)—,    carbocyclylalkyl-C(═O)—, heterocarbocyclylalkyl-C(═O)—, C₁-C₁₀    alkyl-S(═O)₂—, carbocyclyl-S(═O)₂—, heterocarbocyclyl-S(═O)₂—,    carbocyclylalkyl-S(═O)₂—, heterocarbocyclylalkyl-S(═O)₂—, C₁-C₁₀    alkyl-NHC(═O)—, carbocyclyl-NHC(═O)—, heterocarbocyclyl-NHC(═O)—,    carbocyclylalkyl-NHC(═O)—, heterocarbocyclylalkyl-NHC(═O)—, C₁-C₁₀    alkyl-OC(═O)—, carbocyclyl-OC(═O)—, heterocarbocyclyl-OC(═O)—,    carbocyclylalkyl-OC(═O)—, heterocarbocyclylalkyl-OC(═O)—, or an    amino protecting group; wherein R¹⁰ is optionally substituted with    1, 2 or 3 R²³;-   alternatively, R⁹ and R¹⁰ together with the N atom to which they are    attached form a heterocarbocyclyl group;-   R¹¹ is C₁-C₆ alkyl, aryl, or NR¹²R¹³;-   R¹² and R¹³ are, independently, H, C₁-C₁₀ alkyl, carbocyclyl,    heterocarbocyclyl, or an amino protecting group;-   alternatively, R¹² and R¹³ together with the N atom to which they    are attached form a heterocarbocyclyl group;-   Z is O or S;-   Q is —B(OH)₂, —B(OR¹⁴)₂, or a cyclic boronic ester wherein said    cyclic boronic ester contains from 6 to 20 carbon atoms and contains    at least one cycloalkyl moiety;-   R¹⁴ is H, C₁-C₄ alkyl, or cycloalkyl;-   X is R^(A)C(═O)—, R^(A)NHC(═O)—, R^(A)S(═O)₂—, R^(A)C(═O)—,    R^(A)SC(═O)—, or R^(A);-   R^(A) is C₁-C₂₀ alkyl optionally substituted with R²⁰; C₂-C₂₀    alkenyl optionally substituted with R²⁰; C₂-C₂₀ alkynyl optionally    substituted with R²⁰; carbocyclyl optionally substituted with 1-5    R²¹; or heterocarbocyclyl optionally substituted with 1-5 R²¹;-   R²⁰ is selected from the group consisting of:    -   —CN, halo, haloalkyl-, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄        alkynyl, —CO₂H, —C(═O)CO₂H, —C(═O)NH₂, —C(═O)H, —S(═O)NH₂,        —S(═O)₂NH₂, —OH, —SH, —NH₂, —NH(alkyl), —N(alkyl)₂, —NHC(═O)NH₂,        —NHC(═O)R^(20a), —NHC(═O)OR^(20a), —OR^(20a), —SR^(20a),        —S(═O)R^(20a), —S(═O)₂R^(20a), —S(═O)₂—NHR^(20a),        —SC(═O)R^(20a), —C(═O)R^(20a), —C(═O)NHR^(20a), —C(═O)O—R^(20a),        —NHS(═O)₂R^(20a), —NHR^(20b), phthalimido, —(O-alkyl)_(r),        —O-alkyl-OH, —(O-alkyl)_(r)-OH, —OR^(20c), —SR^(20c),        —O-alkyl-R^(20c), —S-alkyl-R^(20c), —S(═O)—R^(20c),        —S(═O)₂—R^(20c), —S(═O)₂—NHR^(20c), —SC(═O)R^(20c),        —C(═O)R^(20c), —C(═O)OR^(20c), —C(═O)NHR^(20c), carbocyclyl        optionally substituted with 1-5 R²¹; and heterocarbocyclyl        optionally substituted with 1-5 R²¹;-   R^(20a) is C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, or C₂-C₂₀ alkynyl; wherein    said alkyl, alkenyl, or alkynyl is optionally substituted by one or    more halo, C₁-C₄ alkyl, aryl, heteroaryl or —NHR^(20b);-   R^(20b) is an amino protecting group;-   R^(20c) is carbocyclyl optionally substituted with 1-5 R²²; or    heterocarbocyclyl optionally substituted with 1-5 R²²;-   R²¹ is selected from the group consisting of:    -   C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, C₁-C₂₀ alkoxy,        C₁-C₂₀ thialkoxy, —OH, —CN, halo, haloalkyl, —NH₂, —NH(alkyl),        —N(alkyl)₂, —NHC(═O)O-alkyl, —NHC(═O)alkyl, —C(═O)O-alkyl,        —C(═O)alkyl, —S(═O)-alkyl, —S(═O)₂-alkyl, —S(═O)-aryl,        —S(═O)₂-aryl, carbocyclyl optionally substituted with 1-5 R²²,        and heterocarbocyclyl optionally substituted with 1-5 R²²;-   R²² is selected from the group consisting of:    -   C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, phenyl, halo,        haloalkyl, alkoxy, thialkoxy, amino, alkylamino, dialkylamino,        carboxyl, alkyl-OC(═O)—, alkyl-C(═O)—, aryl-OC(═O)—,        alkyl-OC(═O)NH—, aryl-OC(═O)NH—, alkyl-C(═O)NH—, alkyl-C(═O)O—,        (alkyl-O)_(r)-alkyl, HO-(alkyl-O)_(r)-alkyl-, —OH, —SH, —CN,        —N₃, —CNO, —CNS, alkyl-S(═O)—, alkyl-S(═O)₂—, H₂NS(═O)—, and        H₂NS(═O)₂—;-   R²³ is selected from the group consisting of:    -   C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, F, Cl, Br, I,        haloalkyl, —NH₂, —NHR^(23a), —N(R^(23a))₂, —N₃, —NO₂, —CN, —CNO,        —CNS, —C(═O)OR^(23a), —C(═O)R^(23a), —OC(═O)R^(23a),        —N(R^(23a))C(═O)R^(23a), —C(═O)N(R^(23a))₂, ureido, —OR^(23a),        —SR^(23a), —S(═O)₂—(C₁-C₆ alkyl), —S(═O)₂-aryl, and        —S(═O)₂—N(R^(23a))₂;-   R^(23a) is H or C₁-C₆ alkyl;-   alternatively, two R^(23a) may be combined, together with the N atom    to which they are attached, to form a 5 to 7 membered heterocyclic    group; and-   r is 2, 3, 4, 5, 6, 7, 8, 9, or 10;-   with the proviso that when X is R^(A)C(═O)—, R^(A) is a C₄-C₁₅    straight-chained alkyl substituted with R²⁰, and R²⁰ is —CN, —CO₂H,    —C(═O)0—R^(20a), —NHS(═O)₂R^(20a), —NHC(═O)R^(20a), —NHR^(20b), or    phthalimido; then R² is not —(CH₂)_(a)CH₂NHC(═NR⁴)NH—Y, wherein Y is    H, —CN, —NO₂, or a guanidino protecting group.

In further embodiments, the present invention provides compounds ofFormula (I)

or pharmaceutically acceptable salt, stereoisomeric or tautomeric formthereof, wherein:

-   R¹ is C₁-C₄ alkyl;-   R² is —(CH₂)_(a)CH₂NHC(═NH)NH—Y, —(CH₂)_(c)CH₂NHCONH₂, or    —(CH₂)_(d)CH(R⁷)NR⁹R¹⁰;-   a is 1, 2, or 3;-   c is 1, 2, or 3;-   d is 0 or 1;-   R⁷ is H or methyl;-   R⁹ is H or C₁-C₁₀ alkyl;-   R¹⁰ is H, C₁-C₁₀ alkyl, or an amino protecting group;-   Y is H, CN, or NO₂;-   Q is —B(OH)₂, pinanediol boronic ester, bicyclohexyl-1,1′-diol    boronic ester, or 1,2-dicyclohexyl-ethane-1,2-diol boronic ester;-   X is R^(A)C(═O)—, R^(A)NHC(═O)—, R^(A)S(═O)₂—, R^(A)C(═O)—,    R^(A)SC(═O)—, or R^(A);-   R^(A) is C₁-C₂₀ alkyl optionally substituted with R²⁰; C₂-C₂₀    alkenyl optionally substituted with R²⁰; C₂-C₂₀ alkynyl optionally    substituted with R²⁰; carbocyclyl optionally substituted with 1-5    R²¹; or heterocarbocyclyl optionally substituted with 1-5 R²¹;-   R²⁰ is selected from the group consisting of:    -   —CN, halo, haloalkyl-, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄        alkynyl, —CO₂H, —C(═O)CO₂H, —C(═O)NH₂, —C(═O)H, —S(═O)NH₂,        —S(═O)₂NH₂, —OH, —SH, —NH₂, —NH(alkyl), —N(alkyl)₂, —NHC(═O)NH₂,        —NHC(═O)R^(20a), —NHC(═O)OR^(20a), —OR^(20a), —SR^(20a),        —S(═O)R^(20a), —S(═O)₂R^(20a), —S(═O)₂—NHR^(20a),        —SC(═O)R^(20a), —C(═O)R^(20a), —C(═O)NHR^(20a), —C(═O)O—R^(20a),        —NHS(═O)₂R^(20a), —NHR^(20b), phthalimido, —(O-alkyl)_(r),        —O-alkyl-OH, —(O-alkyl)_(r)-OH, —OR^(20c), —SR^(20c),        —O-alkyl-R^(20c), —S-alkyl-R^(20c), —S(═O)—R^(20c),        —S(═O)₂—R^(20c), —S(═O)₂—NHR^(20c), —SC(═O)R^(20c),        —C(═O)R^(20c), —C(═O)OR^(20c), —C(═O)NHR^(20c), carbocyclyl        optionally substituted with 1-5 R²¹; and heterocarbocyclyl        optionally substituted with 1-5 R²¹;-   R^(20a) is C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, or C₂-C₂₀ alkynyl; wherein    said alkyl, alkenyl, or alkynyl is optionally substituted by one or    more halo, C₁-C₄ alkyl, aryl, heteroaryl or —NHR^(20b);-   R^(20b) is an amino protecting group;-   R^(20c) is carbocyclyl optionally substituted with 1-5 R²²; or    heterocarbocyclyl optionally substituted with 1-5 R²²;-   R²¹ is selected from the group consisting of:    -   C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, C₁-C₂₀ alkoxy,        C₁-C₂₀ thialkoxy, —OH—CN, halo, haloalkyl, —NH₂, —NH(alkyl),        —N(alkyl)₂, —NHC(═O)O-alkyl, —NHC(═O)alkyl, —C(═O)O-alkyl,        —C(═O)alkyl, —S(═O)-alkyl, —S(═O)₂-alkyl, —S(═O)-aryl,        —S(═O)₂-aryl, carbocyclyl optionally substituted with 1-5 R²²,        and heterocarbocyclyl optionally substituted with 1-5 R²²;-   R²² is selected from the group consisting of:    -   C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, phenyl, halo,        haloalkyl, alkoxy, thialkoxy, amino, alkylamino, dialkylamino,        carboxyl, alkyl-OC(═O)—, alkyl-C(═O)—, aryl-OC(═O)—,        alkyl-OC(═O)NH—, aryl-OC(═O)NH—, alkyl-C(═O)NH—, alkyl-C(═O)O—,        (alkyl-O)_(r)-alkyl, HO-(alkyl-O)_(r)-alkyl-, —OH, —SH, —CN,        —N₃, —CNO, —CNS, alkyl-S(═O)—, alkyl-S(═O)₂—, H₂NS(═O)—, and        H₂NS(═O)₂—; and-   r is 2, 3, 4, or 5;-   with the proviso that when X is R^(A)C(═O)—, R^(A) is a C₄-C₁₅    straight-chained alkyl substituted with R²⁰, and R²⁰ is —CN, —CO₂H,    —C(═O)O—R^(20a), —NHS(═O)₂R^(20a), —NHC(═O)R^(20a), —NHR^(20b), or    phthalimido; then R² is not —(CH₂)_(a)CH₂NHC(═NR⁴)NH—Y, wherein Y is    H, —CN, or —NO₂.

In yet further embodiments, the present invention provides compound ofFormula (I) or pharmaceutically acceptable salt, stereoisomeric ortautomeric form thereof, wherein:

-   R¹ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, or C₃-C₇    cycloalkyl;-   R² is —CH₂NH₂ or —CH₂NR⁹R¹⁰;-   R⁹ is H or C₁-C₁₀ alkyl;-   R¹⁰ is H, C₁-C₁₀ alkyl, carbocyclyl, heterocarbocyclyl, C₁-C₁₀    alkyl-C(═O)—, carbocyclyl-C(═O)—, heterocarbocyclyl-C(═O)—,    carbocyclylalkyl-C(═O)—, heterocarbocyclylalkyl-C(═O)—, C₁-C₁₀    alkyl-S(═O)₂—, carbocyclyl-S(═O)₂—, heterocarbocyclyl-S(═O)₂—,    carbocyclylalkyl-S(═O)₂—, heterocarbocyclylalkyl-S(═O)₂—, C₁-C₁₀    alkyl-NHC(═O)—, carbocyclyl-NHC(═O)—, heterocarbocyclyl-NHC(═O)—,    carbocyclylalkyl-NHC(═O)—, heterocarbocyclylalkyl-NHC(═O)—, C₁-C₁₀    alkyl-OC(═O)—, carbocyclyl-OC(═O)—, heterocarbocyclyl-OC(═O)—,    carbocyclylalkyl-OC(═O)—, heterocarbocyclylalkyl-OC(═O)—, or an    amino protecting group; wherein R¹⁰ is optionally substituted with    1, 2 or 3, R²³;-   alternatively, R⁹ and R¹⁰ together with the N atom to which they are    attached form a heterocarbocyclyl group;-   Q is —B(OH)₂, —B(OR¹⁴)₂, or a cyclic boronic ester wherein said    cyclic boronic ester contains from 2 to 20 carbon atoms, and,    optionally, a heteroatom which can be N, S, or O;-   R¹⁴ is H, C₁-C₄ alkyl, cycloalkyl, cycloalkylalkyl, aryl, or    aralkyl;-   X is R^(A)C(═O)—, R^(A)NHC(═O)—, R^(A)S(═O)₂—, R^(A)C(═O)—,    R^(A)SC(═O)—, or R^(A);-   R^(A) is C₁-C₂₀ alkyl optionally substituted with R²⁰; C₂-C₂₀    alkenyl optionally substituted with R²⁰; C₂-C₂₀ alkynyl optionally    substituted with R²⁰; carbocyclyl optionally substituted with 1-5    R²¹; or heterocarbocyclyl optionally substituted with 1-5 R²¹;-   R²⁰ is selected from the group consisting of:    -   —CN, halo, haloalkyl-, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄        alkynyl, —CO₂H, —C(═O)CO₂H, —C(═O)NH₂, —C(═O)H, —S(═O)NH₂,        —S(═O)₂NH₂, —OH, —SH, —NH₂, —NH(alkyl), —N(alkyl)₂, —NHC(═O)NH₂,        —NHC(═O)R^(20a), —SC(═O)R^(20a), —C(═O)R^(20a), —C(═O)NHR^(20a),        —S(═O)₂—NHR^(20a), —SC(═O)^(20a), —C(═O)R^(20a),        —C(═O)NHR^(20a), —C(═O)O—R^(20a), —NHS(═O)₂R^(20a), —NHR^(20b),        phthalimido, —(O-alkyl)_(r), —O-alkyl-OH, —(O-alkyl)_(r)-OH,        —OR^(20c), —SR^(20c), —O-alkyl-R^(20c), —S-alkyl-R^(20c),        —S(═O)—R^(20c), —S(═O)₂—R^(20c), —S(═O)₂—NHR^(20c),        —SC(═O)R^(20c), —C(═O)R^(20c), —C(═O)NHR^(20c), carbocyclyl        optionally substituted with 1-5 R²¹; and heterocarbocyclyl        optionally substituted with 1-5 R²¹;-   R^(20a) is C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, or C₂-C₂₀ alkynyl; wherein    said alkyl, alkenyl, or alkynyl is optionally substituted by one or    more halo, C₁-C₄ alkyl, aryl, heteroaryl or —NHR^(20b);-   R^(20b) is an amino protecting group;-   R^(20c) is carbocyclyl optionally substituted with 1-5 R²²; or    heterocarbocyclyl optionally substituted with 1-5 R²²;-   R²¹ is selected from the group consisting of:    -   C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, C₁-C₂₀ alkoxy,        C₁-C₂₀ thialkoxy, —OH—CN, halo, haloalkyl, —NH₂, —NH(alkyl),        —N(alkyl)₂, —NHC(═O)O-alkyl, —NHC(═O)alkyl, —C(═O)O-alkyl,        —C(═O)alkyl, —S(═O)-alkyl, —S(═O)₂-alkyl, —S(═O)-aryl,        —S(═O)₂-aryl, carbocyclyl optionally substituted with 1-5 R²²,        and heterocarbocyclyl optionally substituted with 1-5 R²²;-   R²² is selected from the group consisting of:    -   C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, phenyl, halo,        haloalkyl, alkoxy, thialkoxy, amino, alkylamino, dialkylamino,        carboxyl, alkyl-OC(═O)—, alkyl-C(═O)—, aryl-OC(═O)—,        alkyl-OC(═O)NH—, aryl-OC(═O)NH—, alkyl-C(═O)NH—, alkyl-C(═O)O—,        (alkyl-O)_(r)-alkyl, HO-(alkyl-O)_(r)-alkyl-, —OH, —SH, —CN,        —N₃, —CNO, —CNS, alkyl-S(═O)—, alkyl-S(═O)₂—, H₂NS(═O)—, and        H₂NS(═O)₂—;-   R²³ is selected from the group consisting of:    -   C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, F, Cl, Br, I,        haloalkyl, —NH₂, —NHR^(23a), —N(R^(23a))₂, —N₃, —NO₂, —CN, —CNO,        —CNS, —C(═O)OR^(23a), —C(═O)R^(23a), —OC(═O)R^(23a),        —N(R^(23a))C(═O)R^(23a), —C(═O)N(R^(23a))₂, ureido, —OR^(23a),        —SR^(23a), —S(═O)₂—(C₁-C₆ alkyl), —S(═O)₂-aryl, and        —S(═O)₂—N(R^(23a))₂;-   R^(23a) is H or C₁-C₆ alkyl;-   alternatively, two R^(23a) may be combined, together with the N atom    to which they are attached, to form a 5 to 7 membered heterocyclic    group; and-   r is 2, 3, 4, or 5.

In yet further embodiments, the present invention provides compounds ofFormula (I) or pharmaceutically acceptable salt, stereoisomeric ortautomeric form thereof, wherein:

-   R¹ is C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, or C₃-C₇    cycloalkyl;-   R² is H;-   Q is —B(OH)₂, —B(OR¹⁴)₂, or a cyclic boronic ester wherein said    cyclic boronic ester contains from 2 to 20 carbon atoms, and,    optionally, a heteroatom which can be N, S, or O;-   R¹⁴ is H, C₁-C₄ alkyl, cycloalkyl, cycloalkylalkyl, aryl, or    aralkyl;-   X is R^(A)C(═O)—, R^(A)NHC(═O)—, R^(A)S(═O)₂—, R^(A)C(═O)—,    R^(A)SC(═O)—, or R^(A);-   R^(A) is C₁-C₂₀ alkyl optionally substituted with R²⁰; C₂-C₂₀    alkenyl optionally substituted with R²⁰; C₂-C₂₀ alkynyl optionally    substituted with R²⁰; carbocyclyl optionally substituted with 1-5    R²²; or heterocarbocyclyl optionally substituted with 1-5 R²²;-   R²⁰ is selected from the group consisting of:    -   —OR^(20a), —SR^(20a), —S(═)R^(20a), —S(═O)₂R^(20a),        —S(═O)₂—NHR^(20a), —SC(═O)R^(20a), —C(═O)R^(20a),        —C(═O)NHR^(20a), —C(═O)O—R^(20a), phthalimido, —(O-alkyl)_(r),        —O-alkyl-OH, —(O-alkyl)_(r)-OH, —OR^(20c), —SR^(20c),        —O-alkyl-R^(20c), —S-alkyl-R^(20c), —S(═O)—R^(20c),        —S(═O)₂—R^(20c), —S(═O)₂—NHR^(20c), —SC(═O)R^(20c),        —C(═O)R^(20c), —C(═O)OR^(20c), —C(═O)NHR^(20c), carbocyclyl        optionally substituted with 1-5 R²²; and heterocarbocyclyl        optionally substituted with 1-5 R²²;-   R^(20a) is C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, or C₂-C₂₀ alkynyl; wherein    said alkyl, alkenyl, or alkynyl is optionally substituted by one or    more halo, C₁-C₄ alkyl, aryl, heteroaryl or —NHR^(20b);-   R^(20c) is carbocyclyl optionally substituted with 1-5 R²²; or    heterocarbocyclyl optionally substituted with 1-5 R²²;-   R²² is selected from the group consisting of:    -   C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, phenyl, halo,        haloalkyl, alkoxy, thialkoxy, amino, alkylamino, dialkylamino,        carboxyl, alkyl-OC(═O)—, alkyl-C(═O)—, aryl-OC(═O)—,        alkyl-OC(═O)NH—, aryl-OC(═O)NH—, alkyl-C(═O)NH—, alkyl-C(═O)O—,        (alkyl-O)_(r)-alkyl, HO-(alkyl-O)_(r)-alkyl-, —OH, —SH, —CN,        —N₃, —CNO, —CNS, alkyl-S(═O)—, alkyl-S(═O)₂—, H₂NS(═O)—, and        H₂NS(═O)₂—; and-   r is 2, 3, 4, 5, 6, 7, 8, 9, or 10.

In yet further embodiments:

-   X is R^(A)C(═O)—, R^(A)NHC(═O)—, R^(A)S(O)₂—, or R^(A); R^(A) is    C₁-C₁₄ alkyl optionally substituted with R²⁰; R²⁰ is    —(O-alkyl)_(r)-OH or —(O-alkyl)_(r)-(O-alkyl); and r is 1, 2, 3, 4,    or 5. In further embodiments, the O-alkyl is methoxy, ethoxy, or    propoxy.

In yet further embodiments, the present invention provides compounds ofFormula (I) or pharmaceutically acceptable salts, stereoisomeric ortautomeric forms thereof, wherein:

-   R¹ is 2-propyl;-   R² is —CH₂CH₂CH₂NHC(═NH)NH—NO₂, —CH₂CH₂CH₂NHC(═O)NH₂, —CH(CH₃)OH,    —CH₂CONH₂, —CH₂NH₂, or —CH₂NR⁹R¹⁰;-   R⁹ is H;-   R¹⁰ is methyl-C(═O)—, ethyl-C(═O)—, propyl-C(═O)—, butyl-C(═O)—,    pentyl-C(═O)—, 2-(ethoxycarbonyl)ethyl-C(═O)—,    4-methyl-phenyl-C(═O)—, cyclopropyl-C(═O)—, 4-fluoro-phenyl-C(═O)—,    4-H₂NSO₂-phenyl-C(═O)—, 4-H₃CSO₂-phenyl-C(═O)—,    4-phenyl-phenyl-C(═O)—, 3,4-dimethoxy-benzyl-C(═O)—,    3-pyridinyl-C(═O)—, 2-(hydroxy)-pyridin-3-yl-C(═O)—,    6-(morpholino)-pyridin-3-yl-C(═O)—,    2-(pyridin-4-yl)thiazol-4-yl-C(═O)—, 2-pyrazinyl-C(═O)—,    2,5-dimethyl-pyrazolyl-C(═O)—, N-methyl-2-pyrrolyl-C(═O)—,    2-pyrrolidinyl-C(═O)—, 2-thiophenyl-C(═O)—, 5-isoxazolyl-C(═O)—,    4-(tetrazol-5-yl)phenyl-C(═O)—, (5-tetrazolyl)CH₂—C(═O)—,    N—H₃CSO₂-piperidinyl-C(═O)—, butyl-OC(═O)—, (benzyl)-OC(═O)—,    (9-fluorenylmethyl)-OC(═O)—, pentyl-NHC(═O)—, propyl-NHC(═O)—,    phenyl-NHC(═O)—, 4-methyl-phenyl-NHC(═O)—, methyl-S(═O)₂—,    4-fluoro-phenyl-S(═O)₂—, 4-cyano-phenyl-S(═O)₂—,    1-methyl-imidazol-4-yl-S(═O)₂—, 2-thiophenyl-S(═O)₂—,    (4-methyl-phenyl)-NHC(═O)NH—S(═O)₂—, and    (4-methyl-phenyl)-S(═O)₂NHC(═O)—,-   alternatively, R⁹ and R¹⁰ together with the N atom to which they are    attached form pyrrolyl or pyrazolyl;-   Q is —B(OH)₂, pinanediol boronic ester, bicyclohexyl-1,1′-diol    boronic ester, or 1,2-dicyclohexyl-ethane-1,2-diol boronic ester;-   X is R^(A)C(═O)—, R^(A)NHC(═O)—, R^(A)S(═O)₂—, or R^(A)C(═O)—;-   R^(A) is CH₃—, C₂H₅—, C₃H₇—, C₄H₉—, C₅H₁₁—, C₆H₁₃—, C₇H₁₅—, C₈H₁₇—,    C₉H₁₉—, C₁₀H₂₁—, C₁₁H₂₃—, C₁₂H₂₅—, C₁₃H₂₇—, adamantyl-,    bicycloheptanyl-, C₁₋₃ alkyl substituted with R²⁰; C₂₋₁₀ alkenyl    substituted with R²⁰; cyclopropyl substituted with 0-3 R²¹;    cyclopentyl substituted with 0-2 R²¹; cyclohexyl substituted with    0-2 R²¹; phenyl substituted with 0-3 R²¹; naphthyl-substituted with    0-2 R²¹; pyrazinyl substituted with 0-1 R²¹; quinolinyl substituted    with 0-1 R²¹; imidazolyl substituted with 0-1 R²¹; tetrahydrofuranyl    substituted with 0-1 R²¹; oxothiazolidinyl substituted with 0-1 R²¹;    benzothiazolyl substituted with 0-1 R²¹; thiazolyl substituted with    0-2 R²¹; furanyl substituted with 0-2 R²¹; pyrrolidinyl substituted    with 0-1 R²¹; piperidinyl substituted with 0-1 R²¹; piperazinyl    substituted with 0-1 R²¹; or pyridinyl substituted with 0-1 R²¹;-   R²⁰ is selected from the group consisting of:    -   hydroxy-, methoxy-, ethoxy-, propoxy-, butoxy-, pentoxy-,        hexyloxy-, heptyloxy-, octyloxy-, methoxyethoxy-,        methoxyethoxyethoxy-, methyl-S—, ethyl-S—, octyl-S—,        methyl-C(═O)S—, (acetylamino)methyl-S—, amino-, methylamino-,        dimethylamino-, methyl-C(═O)—, phenyl-C(═O)—,        (H₃CSO₂)phenyl-C(═O)—, thiophenyl-C(═O)—, methyl-OC(═O)—,        ethyl-OC(═O)—, butyl-OC(═O)NH—, methyl-C(═O)NH—,        methoxyethoxy-methyl-C(═O)NH—, H₂NC(═O)—, methyl-NHC(═O)—,        ethyl-NHC(═O)—, propyl-NHC(═O)—, phenyl-NHC(═O)—, H₂NC(═O)NH—,        H₂NS(═O)₂—, octyl-S(═O)₂—, phenyl-S(═O)₂—, methylphenyl-S(═O)₂—,        thiophenyl-S(═O)₂—, cyclopentyl-, cyclohexyl-, cycloheptyl-,        adamantyl-, bicycloheptanyl-, cyclopentenyl-, phenyl-,        methoxy-phenyl-, methyl-phenyl-, dimethyl-phenyl-,        ethyl-phenyl-, propyl-phenyl-, butyl-phenyl-, fluoro-phenyl-,        difluoro-phenyl-, chloro-phenyl-, bromo-phenyl-, iodo-phenyl-,        dimethylamino-phenyl-, cyclohexyloxy-,        2-isopropyl-5-methyl-cyclohexyloxy-, naphthyl-,        methoxynaphthyl-, naphthyloxy-, phenoxy-, (methyl-phenyl)oxy-,        (ethyl-phenyl)oxy-, (propyl-phenyl)oxy-, (butyl-phenyl)oxy-,        (fluoro-phenyl)oxy-, (chloro-phenyl)oxy-, (bromo-phenyl)oxy-,        naphthyl-S—, benzyl-S—, (methyl-phenyl)methyl-S—,        pyrimidinyl-S—, piperidinyl-, N-methyl-piperidinyl-,        N-propyl-piperidinyl-, phthalimido-, thiophenyl-,        methyl-thiophenyl-, imidazolyl-, furnayl-, tetrazolyl-,        oxopyrrolidinyl-, indolyl-, and methyl-indolyl-; and-   R²¹ is selected from the group consisting of:    -   methyl-, ethyl-, propyl-, butyl-, pentyl-, hexyl-, heptyl-,        ethenyl-, propenyl-, butenyl-, methoxy-, ethoxy-, propoxy-,        phenoxy-, fluoro-, chloro-, bromo-, methyl-C(═O)—,        butyl-OC(═O)—, butyl-OC(═O)NH—, phenyl-, methoxyphenyl-,        fluorophenyl-, chlorophenyl-, bromophenyl-, pyrrolyl-, and        pyridinyl-.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination.

As used herein, the phrase “boronic acid” refers to a compoundcontaining a B(OH)₂ moiety. In some embodiments, boronic acid compoundscan form oligomeric anhydrides by dehydration of the boronic moiety. Forexample, Snyder, et al., J. Am. Chem. Soc., 1958, 80, 3611 reportoligomeric arylboronic acids. Thus, unless otherwise indicated, “boronicacid”, or a chemical formula containing a —B(OH)₂ moiety, is intended toencompass free boronic acids, oligomeric anhydrides, including but notlimited to, dimers, trimers, tetramers, and mixtures thereof.

As used herein, “boronic acid anhydride” or “boronic anhydride” refersto a compound formed by the combination of two or more molecules of aboronic acid compound of Formula (I), with loss of one or more watermolecules from the boronic acid moieties. When contacted with water, theboronic acid anhydride compound can be hydrated to release free boronicacid compound. In some embodiments, the boronic acid anhydride structurecan contain two, three, four, or more boronic acid units and can have acyclic or linear configuration. In some embodiments, the boronic acidanhydride compound exists substantially in a single oligomeric form;however, boronic acid anhydrides also encompass mixtures of differentoligomeric boronic acid anhydride as well as free boronic acids.

Non-limiting examples of boronic acid anhydrides of the inventioninclude compounds of Formula (II) and (III) where G is a moiety ofFormula (IV) and t is 0 to 10 or 1, 2, 3, or 4.

In some embodiments, at least about 80% of boronic acid present in aboronic acid anhydride compound exists in a single oligomeric anhydrideform. In further embodiments, at least about 85, about 90, about 95, orabout 99% of the boronic acid present in the boronic acid anhydrideexists in a single oligomeric anhydride form. In some embodiments, theboronic acid anhydride compound consists essentially of a singleoligomeric boronic acid anhydride. In yet further embodiments, theboronic acid anhydride compound consists of a single oligomeric boronicacid anhydride. In further embodiments, the boronic acid anhydridecompound contains a boroxine of Formula (III), wherein t is 1.

Boronic acid anhydride compounds can be prepared from the correspondingboronic acid compound by exposure to dehydrating conditions, including,for example, crystallization, lyophilization, exposure to heat, and/orexposure to a drying agent. Some suitable crystallization solventsinclude ethyl acetate, dichloromethane, hexanes, ether, benzene,acetonitrile, ethanol, and mixtures thereof.

As used herein, the phrase “boronic ester” or “boronic acid ester”refers to an ester derivative of a boronic acid compound. As usedherein, “cyclic boronic ester” is intended to mean a stable cyclicboronic moiety of general formula —B(OR)(OR) wherein the two Rsubstituents are linked together forming a cyclic moiety (e.g., 3- to10-membered cycloalkyl group) optionally further substituted with one ormore substituents or fused with (sharing at least one bond) one or morefurther carbocyclyl or heterocarbocyclyl groups. The cyclic boronicester can contain from 2 to 20 carbon atoms, and optionally, aheteroatom which can be N, S, or O. Cyclic boronic esters are well knownin the art. Examples of cyclic boronic esters include, but are notlimited to, pinanediol boronic ester, pinacol boronic ester,1,2-ethanediol boronic ester, 1,3-propanediol boronic ester,1,2-propanediol boronic ester, 2,3-butanediol boronic ester,1,1,2,2-tetramethylethanediol boronic ester, 1,2-diisopropylethanediolboronic ester, 5,6-decanediol boronic ester, 1,2-dicyclohexylethanediolboronic ester, bicyclohexyl-1,1′-diol, diethanolamine boronic ester, and1,2-diphenyl-1,2-ethanediol boronic ester.

In some embodiments, the “cyclic boronic ester” has Formula (II-a):

wherein:

-   -   D is absent, O, S, NR¹⁶, or CR^(15e)R^(15f);    -   R^(15a), R^(15b), R^(15c), R^(15d), R^(15e), R^(15f) are each,        independently, H, C₁-C₁₀ alkyl, C₃-C₇ cycloalkyl, aryl or        heteroaryl, wherein said C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, aryl        or heteroaryl are each optionally substituted by 1, 2, 3 or 4        halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, OH, amino,        alkylamino, dialkylamino, aryl, or heteroaryl;    -   or R^(15a) and R^(15b) together with the C atoms to which they        are attached form C₃-C₁₀ cycloalkyl or a 3- to 10-membered        heterocycloalkyl group, each optionally substituted by 1, 2, 3        or 4 halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, OH,        amino, alkylamino, dialkylamino, aryl, or heteroaryl;    -   or R^(15c) and R^(15d) together with the C atoms to which they        are attached form C₃-C₁₀ cycloalkyl or a 3- to 10-membered        heterocycloalkyl group, each optionally substituted by 1, 2, 3        or 4 halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, OH,        amino, alkylamino, dialkylamino, aryl, or heteroaryl;    -   or R^(15b) and R^(15c) together with the C atoms to which they        are attached and the intevening D moiety form aryl, heteroaryl,        C₃-C₁₀ cycloalkyl or a 3- to 10-membered heterocycloalkyl group,        each optionally substituted by 1, 2, 3 or 4 halo, C₁-C₄ alkyl,        C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, OH, amino, alkylamino,        dialkylamino, aryl, or heteroaryl;    -   R¹⁶ is H or C₁-C₆ alkyl; and    -   p and q are each, independently, 1, 2 or 3.

In some embodiments, D is absent.

In some embodiments, D is NR¹⁶.

In some embodiments, D is NH.

In some embodiments, D is CH₂.

In some embodiments, R^(15a) and R^(15b) together with the C atoms towhich they are attached form C₃-C₁₀ cycloalkyl or a 3- to 10-memberedheterocycloalkyl group, each optionally substituted by 1, 2, 3 or 4halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, OH, amino,alkylamino, dialkylamino, aryl, or heteroaryl; and R^(15c) and R^(15d)together with the C atoms to which they are attached form C₃-C₁₀cycloalkyl or a 3- to 10-membered heterocycloalkyl group, eachoptionally substituted by 1, 2, 3 or 4 halo, C₁-C₄ alkyl, C₁-C₄ alkoxy,C₁-C₄ haloalkoxy, OH, amino, alkylamino, dialkylamino, aryl, orheteroaryl.

In some embodiments, R^(15a) and R^(15b) together with the C atoms towhich they are attached form cyclopropyl, cyclobutyl, cyclopenylyl,cyclohexyl or cycloheptyl; and R^(15c) and R^(15d) together with the Catoms to which they are attached form cyclopropyl, cyclobutyl,cyclopenylyl, cyclohexyl or cycloheptyl.

In some embodiments, D is absent and R^(15b) and R^(15c) together withthe C atoms to which they are attached form aryl, heteroaryl, C₃-C₁₀cycloalkyl or a 3- to 10-membered heterocycloalkyl group, eachoptionally substituted by 1, 2, 3 or 4 halo, C₁-C₄ alkyl, C₁-C₄ alkoxy,C₁-C₄ haloalkoxy, OH, amino, alkylamino, dialkylamino, aryl, orheteroaryl.

In some embodiments, D is absent and R^(15b) and R^(15c) together withthe C atoms to which they are attached form C₃-C₁₀ cycloalkyl optionallysubstituted by 1, 2, 3 or 4 halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄haloalkoxy, OH, amino, alkylamino, dialkylamino, aryl, or heteroaryl.

In some embodiments, D is absent and R^(15b) and R^(15c) together withthe C atoms to which they are attached form C₃-C₁₀ cycloalkyl optionallysubstituted by 1, 2, 3 or 4 halo or C₁-C₄ alkyl.

In some embodiments, D is absent and R^(15b) and R^(15c) together withthe C atoms to which they are attached form a C₇-C₁₀ bicyclic cycloalkylgroup optionally substituted by 1, 2, 3 or 4 halo or C₁-C₄ alkyl.

In some embodiments, p and q are each 1.

In some embodiments, at least one of R^(15a), R^(15b), R^(15c), R^(15d)is other than H.

Further examples of “cyclic boronic esters”, as defined herein, include,boronic esters with the following structures:

wherein: W is a substituted or unsubstituted C₄-C₁₀ cycloalkyl ring or asubstituted or unsubstituted phenyl ring; W¹ is, independently at eachoccurrence, a substituted or unsubstituted C₃-C₆ cycloalkyl ring. GroupsR^(15a), R^(15b), R^(15c), R^(15d), R^(15e), R^(15f), p and q are,defined as provided above.

As used herein, the term “alkyl” or “alkylene” is meant to refer to asaturated hydrocarbon group which is straight-chained or branched.Example alkyl groups include methyl (Me), ethyl (Et), propyl (e.g.,n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl,t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl) and the like. Analkyl group can contain from 1 to about 20, from 2 to about 20, from 1to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, orfrom 1 to about 3 carbon atoms.

As used herein, “alkenyl” refers to an alkyl group having one or moredouble carbon-carbon bonds. Example alkenyl groups include ethenyl,propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl,hexadienyl, and the like.

As used herein, “alkynyl” refers to an alkyl group having one or moretriple carbon-carbon bonds. Example alkynyl groups include ethynyl,propynyl, butynyl, pentynyl, and the like.

As used herein, “haloalkyl” refers to an alkyl group having one or morehalogen substituents. Example haloalkyl groups include CF₃, C₂F₅, CHF₂,CCl₃, CHCl₂, C₂Cl₅, and the like. An alkyl group in which all of thehydrogen atoms are replaced with halogen atoms can be referred to as“perhaloalkyl.” Examples perhaloalkyl groups include CF₃ and C₂F₅.

As used herein, “carbocyclyl” groups are saturated (i.e., containing nodouble or triple bonds) or unsaturated (i.e., containing one or moredouble or triple bonds) cyclic hydrocarbon moieties. Carbocyclyl groupscan be mono- or polycyclic. Example carbocyclyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclopentenyl, 1,3-cyclopentadienyl, cyclohexenyl, norbornyl, norpinyl,norcarnyl, adamantyl, phenyl, and the like. Carbocyclyl groups can bearomatic (e.g., “aryl”) or non-aromatic (e.g., “cycloalkyl”). In someembodiments, carbocyclyl groups can have from 3 to about 20, 3 to about10, or 3 to about 7 carbon atoms.

As used herein, “aryl” refers to aromatic carbocyclyl groups includingmonocyclic or polycyclic aromatic hydrocarbons such as, for example,phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and thelike. In some embodiments, aryl groups have from 6 to about 18ring-forming carbon atoms.

As used herein, “cycloalkyl” refers to non-aromatic carbocyclyl groupsincluding cyclized alkyl, alkenyl, and alkynyl groups. Cycloalkyl groupscan include bi- or poly-cyclic ring systems. Example cycloalkyl groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl,norbornyl, norpinyl, norcarnyl, adamantyl, and the like. Also includedin the definition of cycloalkyl are moieties that have one or morearomatic rings fused (i.e., having a bond in common with) to thecycloalkyl ring, for example, benzo derivatives of cyclopentane(indanyl), cyclohexane (tetrahydronaphthyl), and the like. In someembodiments, cycloalkyl groups can have 3, 4, 5, 6, or 7 ring formingcarbon atoms. In some embodiments, cycloalkyl groups can have 0, 1, or 2double or triple ring-forming bonds.

As used herein, “heterocarbocyclyl” groups can be saturated orunsaturated carbocyclyl groups wherein one or more of the ring-formingcarbon atoms of the carbocyclyl group is replaced with a heteroatom suchas O, S, or N. Heterocarbocyclyl groups can be aromatic (e.g.,“heteroaryl”) or non-aromatic (e.g., “heterocycloalkyl”).Heterocarbocyclyl groups can correspond to hydrogenated and partiallyhydrogenated heteroaryl groups. Heterocarbocyclyl groups can contain, inaddition to at least one heteroatom, from about 1 to about 20, about 2to about 10, or about 2 to about 7 carbon atoms and can be attachedthrough a carbon atom or heteroatom. Examples of heterocarbocyclylgroups include morpholino, thiomorpholino, piperazinyl,tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl,1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl,thiazolidinyl, imidazolidinyl, and the like.

As used herein, “heteroaryl” groups are aromatic heterocarbocyclylgroups and include monocyclic and polycyclic aromatic hydrocarbons thathave at least one heteroatom ring member such as sulfur, oxygen, ornitrogen. Heteroaryl groups include, without limitation, pyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl,isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl,oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, and thelike. In some embodiments, heteroaryl groups can have from 3 to about 20ring-forming carbon atoms, and in further embodiments from about 3 toabout 12 ring forming carbon atoms. In some embodiments, heteroarylgroups have 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.

As used herein, “heterocycloalkyl” refers to a non-aromaticheterocarbocyclyl group including cyclized alkyl, alkenyl, and alkynylgroups where one or more of the ring-forming carbon atoms is replaced bya heteroatom such as an O, N, or S atom. Ring-forming carbon andheteroatoms such as S and N can further be oxidized in aheterocycloalkyl moeity. For example, the ring-forming carbon orheteroatom can bear one or two oxo or sufido moieties (e.g., >C═O, >S═O,>S(═O)₂, N→O, etc.). Also included in the definition of heterocycloalkylare moieties that have one or more aromatic rings fused (i.e., having abond in common with) to the nonaromatic heterocyclic ring, for examplephthalimidyl, naphthalimidyl pyromellitic diimidyl, phthalanyl, andbenzo derivatives of saturated heterocycles such as indolene andisoindolene groups. In some embodiments, heterocycloalkyl groups have 3to about 20 ring-forming atoms. In some embodiments, heterocycloalkylgroups have 3, 4, 5, 6, or 7 ring-forming atoms. In some embodiments,heterocycloalkyl groups have 0, 1, or 2 double or triple ring-formingbonds.

As used herein, “halo” or “halogen” includes fluoro, chloro, bromo, andiodo.

As used herein, “alkoxy” refers to an —O-alkyl group. Example alkoxygroups include methoxy, ethoxy, propoxy (e.g., n-propoxy andisopropoxy), t-butoxy, and the like. In some embodiments, alkoxy groupshave from 1 to 20, 1 to 12, 1 to 8, 1 to 6, 1 to 4 or 1 to 3 carbonatoms.

As used herein, “alkoxyalkoxy” refers to an —O-alkyl-O-alkyl group.

As used herein, “thioalkoxy” refers to an alkoxy group in which the Oatom is replaced by an S atom.

As used herein, “aryloxy” refers to an —O-aryl group. An example aryloxygroup is phenoxy.

As used herein, “thioaryloxy” refers to an aryloxy group in which the Oatom is replaced by an S atom.

As used herein, “aralkyl” refers to an alkyl moiety substituted by anaryl group. Example aralkyl groups include benzyl and naphthylmethylgroups. In some embodiments, aralkyl groups have from 7 to 11 carbonatoms.

As used herein, “amino” refers to an —NH₂ group. “Alkylamino” refers toan amino group substituted by an alkyl group and “dialkylamino” refersto an amino group substituted by two alkyl groups. On the contrary,“aminoalkyl” refers to an alkyl group substituted by an amino group.

As used herein, “carbonyl” refers to >C═O.

As used herein, “carboxy” or “carboxyl” refers to —COOH.

As used herein, “hydroxy” refers to —OH.

As used herein, “mercapto” refers to —SH.

As used herein, “ureido” refers to —NHCONH₂.

As used herein, “sulfinyl” refers to >SO.

As used herein, “sulfonyl” refers to >SO₂.

As used herein, “oxy” refers to —O—.

The above chemical terms can be combined to refer to moieties containinga combination of chemical groups. This combination term is generallyread such that a recited term is understood to be a substituent of afollowing term. For example, “alkylcarbonylalkenyl” refers to an alkenylgroup substituted by a carbonyl group which in turn is substituted by analkyl group. The following terms can also exemplify such combinations.

As used herein, “carbocyclylalkyl” refers to an alkyl moiety substitutedby a carbocyclyl group. Example carbocyclylalkyl groups include“aralkyl” (alkyl substituted by aryl) and “cycloalkylalkyl” (alkylsubstituted by cycloalkyl).

As used herein, “carbocyclylalkenyl” refers to an alkenyl moietysubstituted by a carbocyclyl group. Example carbocyclylalkenyl groupsinclude “aralkenyl” (alkenyl substituted by aryl) and“cycloalkylalkenyl” (alkenyl substituted by cycloalkyl).

As used herein, “carbocyclylalkynyl” refers to an alkynyl moietysubstituted by a carbocyclyl group. Example carbocyclylalkynyl groupsinclude “aralkynyl” (alkynyl substituted by aryl) and“cycloalkylalkynyl” (alkynyl substituted by cycloalkyl).

As used herein, “heterocarbocyclylalkyl” refers to an alkyl moietysubstituted by a heterocarbocyclyl group. Example heterocarbocyclylalkylgroups include “heteroarylalkyl” (alkyl substituted by heteroaryl) and“heterocycloalkylalkyl” (alkyl substituted by heterocycloalkyl).

As used herein, “heterocarbocyclylalkenyl” refers to an alkenyl moietysubstituted by a heterocarbocyclyl group. Exampleheterocarbocyclylalkenyl groups include “heteroarylalkenyl” (alkenylsubstituted by heteroaryl) and “heterocycloalkylalkenyl” (alkenylsubstituted by heterocycloalkyl).

As used herein, “heterocarbocyclylalkynyl” refers to an alkynyl moietysubstituted by a heterocarbocyclyl group. Exampleheterocarbocyclylalkynyl groups include “heteroarylalkynyl” (alkynylsubstituted by heteroaryl) and “heterocycloalkynylalkyl” (alkynylsubstituted by heterocycloalkyl).

As used herein, the phrase “protecting group” refers to a chemicalfunctional group that can be selectively appended to and removed fromfunctionalities, such as hydroxyl groups, amino groups, and carboxylgroups. Protecting groups are usually introduced into a chemicalcompound to render such functionality inert to chemical reactionconditions to which the compound is exposed. Any of a variety ofprotecting groups can be employed with the present invention. Aprotecting group of an amino moiety can be referred to as an “aminoprotecting group” and a protecting group of a guanidino moiety can bereferred to as a “guanidino protecting group.” Amino and guanidinoprotecting groups can have the formulas aryl-SO₂—, alkyl-SO₂—,aryl-C(═O)—, aralkyl-C(═O)—, alkyl-C(═O)—, aryl-OC(═O)—,aralkyl-OC(═O)—, alkyl-OC(═O)—, aryl-NHC(═O)—, alkyl-NHC(═O)—, and thelike, wherein said alkyl, aryl and aralkyl groups may be substituted orunsubstituted. Example amino and guanidino protecting groups can alsoinclude t-butyloxycarbonyl (BOC), fluorenylmethoxycarbonyl (Fmoc),benzyloxycarbonyl (Cbz), and a phthalimido group. Other protectinggroups include the following moieties:

Further representative protecting groups can be found in T. W. Green andP. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley &Sons, Inc., New York (1999), which is incorporated herein by referencein its entirety.

As used herein, “substituted” indicates that at least one hydrogen atomof a chemical group is replaced by a non-hydrogen moiety. Examplesubstituents include F, Cl, Br, I, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆,alkynyl, haloalkyl, NR^(E)R^(F), N₃, NO₂, CN, CNO, CNS, C(═O)OR^(E),R^(E)CO, R^(E)C(═O)O, R^(E)CONR^(E), R^(E)R^(F)NCO, ureido, OR^(E),SR^(E), SO₂-alkyl, SO₂-aryl, and SO₂—NR^(E)R^(F), wherein R^(E) andR^(F) are each, independently, H or C₁-C₆ alkyl. Alternatively, R^(E)and R^(F) may be combined, with the nitrogen to which they are attached,to form a 5 to 7 membered heterocyclic ring, for example pyrrolidinyl,piperidinyl, morpholinyl, piperazinyl, and N-methylpiperazinyl. When achemical group herein is “substituted” it may have up to the fullvalance of substitution, provided the resulting compound is a stablecompound or stable structure; for example, a methyl group may besubstituted by 1, 2, or 3 substituents, a methylene group may besubstituted by 1 or 2 substituents, a phenyl group may be substituted by1, 2, 3, 4, or 5 substituents, and the like.

As used herein, “leaving group” refers to any group that can be replacedby a nucleophile upon nucleophilic substitution. Example leaving groupsinclude, halo (F, Cl, Br, I), hydroxyl, alkoxy, mercapto, thioalkoxy,triflate, alkylsulfonyl, substituted alkylsulfonate, arylsulfonate,substituted arylsulfonate, heterocyclosulfonate or trichloroacetimidate.Representative examples include p-(2,4-dinitroanilino)benzenesulfonate,benzenesulfonate, methylsulfonate, p-methylbenzenesulfonate,p-bromobenzenesulfonate, trichloroacetimidate, acyloxy,2,2,2-trifluoroethanesulfonate, imidazolesulfonyl and2,4,6-trichlorophenyl.

As used herein “stable compound” or “stable structure” refers to acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and preferably capable offormulation into an efficacious therapeutic agent. The present inventionis directed only to stable compounds.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically active starting materialsare known in the art, such as by resolution of racemic mixtures or bystereoselective synthesis. Many geometric isomers of olefins, C═N doublebonds, and the like can also be present in the compounds describedherein, and all such stable isomers are contemplated in the presentinvention. Cis and trans geometric isomers of the compounds of thepresent invention are described and may be isolated as a mixture ofisomers or as separated isomeric forms.

In addition to the above, the compounds herein described may haveasymmetric centers which result in one enantiomer of a compound ofFormula (I) demonstrating superior biological activity over the oppositeenantiomer. Both of the configurations are considered part of theinvention. For example, the R2 substituent of a compound of Formula (I)may exist in either an S or R configuration. An example of a preferredenantiomeric configuration of the invention is a compound of Formula(I-s):

but is not intended to be limited to this example. When required,separation of the racemic material can be achieved by methods known inthe art.

Compounds of the invention can also include tautomeric forms, such asketo-enol tautomers. Tautomeric forms can be in equilibrium orsterically locked into one form by appropriate substitution.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present invention include the conventionalnon-toxic salts or the quaternary ammonium salts of the parent compoundformed, for example, from non-toxic inorganic or organic acids. Forexample, such conventional non-toxic salts include those derived frominorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic,phosphoric, nitric and the like; and the salts prepared from organicacids such as acetic, propionic, succinic, glycolic, stearic, lactic,malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic,phenylacetic, glutamic, benzoic, salicylic, sulfanilic,2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, and the like. The pharmaceuticallyacceptable salts of the present invention can be synthesized from theparent compound which contains a basic or acidic moiety by conventionalchemical methods. Generally, such salts can be prepared by reacting thefree acid or base forms of these compounds with a stoichiometric amountof the appropriate base or acid in water or in an organic solvent, or ina mixture of the two; generally, nonaqueous media like ether, ethylacetate, ethanol, isopropanol, or acetonitrile are preferred. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17thed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and in theJournal of Pharmaceutical Science, 66, 2 (1977), the disclosures of eachof which are hereby incorporated by reference.

Synthesis

Compounds of the invention, including salts and solvates thereof, can beprepared using known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynonreactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,i.e., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected.

Preparation of Compounds of the Invention can Involve the Protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons,Inc., New York (1999), which is incorporated herein by reference in itsentirety.

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or ¹³C)infrared spectroscopy, spectrophotometry (e.g., UV-visible), or massspectrometry, or by chromatography such as high performance liquidchromatography (HPLC) or thin layer chromatography.

Compounds of the invention can be prepared according to methods forpreparing aminoboronic acids, esters thereof, and related compoundsdescribed in the art, such as in U.S. Pat. No. 4,537,773, and in U.S.Pat. No. 5,614,649, each of which is incorporated herein by reference inits entirety. In some embodiments, the present compounds can be preparedby the sequential coupling of three fragment components (F1, F2, andF3).

F1 Fragment

Synthesis of compounds of the invention can involve a boron-containingfragment (F1) having a structure indicated by Formula (A).

The boronic ester moiety of F1 can include, for example, a diol estersuch as is indicated by the loop connecting oxygen atoms in Formula (A).

Stereochemistry at the carbon atom alpha to the boron atom in Formula(A) can be controlled using an asymmetric boronic ester group in thepreparation of F1. For example, pinanediol esters of boronic acid canfacilitate the preparation or stereochemically pure, or substantiallystereochemically pure, F1 fragment. As an example, the F1 fragment canbe prepared by reacting a compound of Formula (B) (showing a pinanediolboronic ester obtained from (+)-pinanediol) with a strong base (e.g.,lithium diisopropylamide or lithium dicyclohexylamide) in the presenceof dichloromethane or dibromomethane, followed by addition of a Lewisacid, (e.g., ZnCl₂, ZnBr₂, or FeCl₃) to yield a compound of Formula (C)(where L is halo) having a newly introduced stereocenter at the carbonalpha to the boron.

The compound of Formula (C) can, in turn, be reacted with an alkaliamide (e.g., lithium bis(trimethylsilyl)amide, sodiumbis(trimethylsilyl)amide, and potassium bis(trimethylsilyl)amide) orother nucleophile that effectively inverts the newly formed stereocenter(such as by an SN2 type mechanism) and introduces an amine group (NR₂)in place of the halo group (e.g., chloro), forming a compound of Formula(D) (where R can be, e.g., alkyl, Si(alkyl)₃, aryl, or aralkyl).

The compound of Formula (D) can be further reacted with an agent capableof converting the NR₂ group to NH₂, or salt thereof, to form an F1fragment substantially capable of coupling with a further fragmentthrough the amine. A suitable agent for converting the NR₂ group to NH₂can be a protic acid such as HCl such as when R is a silyl group (e.g.,trimethylsilyl).

The compound of Formula (B) can also be prepared according to a two stepprocedure involving reaction of a trialkoxyborane, preferablytriisopropoxyborane, with (1S,2S,3R,5S)-(+) pinanediol, to give amono-alkoxy [(1S,2S,3R,5S)-(+) pinanediol]borane intermediate whereintwo of the alkoxy groups of the trialkoxy borane have been replaced by(1S,2S,3R,5S)-(+) pinanediol. This mixed pinanediol alkoxy borane, uponreaction with the appropriate organometallic derivative, e.g. theGrignard reagent R¹CH₂MgBr or the alkyl lithium R¹CH₂Li, gives compound(B) in good yields and purities. The process starting fromtriisopropoxyborane to give the intermediate mixed pinanediol isopropoxyborane (F) and the compounds of formula (B) is depicted in the followingscheme:

and exemplified in Example A.2, herein.

Accordingly, the present invention is further directed to methods ofpreparing compounds of Formula (II):

wherein the variable constituents are defined hereinabove, by theprocess of a) reacting a diol of Formula (II-b):

with an appropriate trialkoxyborane of Formula (II-a):

wherein each R¹⁷ is, independently, C₁-C₁₀ alkyl or C₃-C₁₀ cycloalkyl;for a time and under conditions suitable for forming a mixedtrialkoxyborane intermediate of Formula (II-c):

and reacting the intermediate of Formula (II-c) with either i) a reagentof formula R¹CH₂MX^(hal), wherein M is a metal and X^(hal) is a halogenatom, or ii) a reagent of formula R¹CH₂Li, for a time and underconditions suitable for forming the compound of Formula (II).

In some embodiments, R¹⁷ is C₁-C₄ alkyl.

In some embodiments, R¹⁷ is isopropyl.

In some embodiments, the diol of Formula (II-b) is pinanediol, pinacol,bicyclohexyl-1,1′-diol, 1,2-ethanediol, 1,3-propanediol,1,2-propanediol, 2,3-butanediol, 1,1,2,2-tetramethylethanediol,1,2-diisopropylethanediol, 5,6-decanediol, 1,2-dicyclohexylethanediol,bicyclohexyl-1,1′-diol, diethanolamine, or 1,2-diphenyl-1,2-ethanediol.

In some embodiments, the diol of Formula (II-b) is pinanediol.

In some embodiments, the Formula R¹CH₂MX^(hal) is a Grignard reagent.

In some embodiments, the Formula R¹CH₂MX^(hal) is R¹CH₂MgBr.

In some embodiments, R¹ is isopropyl.

In some embodiments, the present invention provides a process forpreparing a compound of Formula (II-i):

comprising:a) reacting (1S,2S,3R,5S)-(+)-pinanediol with triisopropoxy borane for atime and under conditions suitable for forming an intermediate ofFormula (II-ii):

and b) reacting the intermediate of Formula (II-ii) with isobutylmagnesium bromide for a time and under conditions suitable for formingthe compound of Formula (II-i).

In some embodiments, the present invention provides a compound ofFormula (II-ii):

The reacting steps can be carried out in any suitable solvent that isnon-reactive with the reagents and products and allows combining ofreagents at lowered temperatures (e.g., temperatures colder than roomtemperature). Suitable solvents include ethers such as dimethoxymethane,tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether,ethylene glycol dimethyl ether, ethylene glycol diethyl ether,diethylene glycol dimethyl ether, diethylene glycol diethyl ether,triethylene glycol dimethyl ether, anisole, or t-butyl methyl ether. Insome embodiments, the ether solvent contains tetrahydrofuran and/ordiethyl ether.

The reactions of the processes described herein can be carried out atappropriate temperatures which can be readily determined by the skilledartisan. Reaction temperatures will depend on, for example, the meltingand boiling points of the reagents and solvent, if present; thethermodynamics of the reaction (e.g., vigorously exothermic reactionsmay need to be carried out at reduced temperatures); and the kinetics ofthe reaction (e.g., a high activation energy barrier may need elevatedtemperatures). “Elevated temperature” refers to temperatures above roomtemperature (about 22° C.) and “reduced temperature” refers totemperatures below room temperature.

In some embodiments, suitable temperatures are reduced temperatures. Thereaction of the trialkoxyborane and diol to prepare a mixedtrialkoxyborane intermediate can be carried out, for example, at atemperature of about −20 to about 10° C. In some embodiments, thereaction of the trialkoxyborane and diol can be carried out at about 0°C. The reaction of the mixed trialkoxyborane intermediate with theorganometallic reagent R¹CH₂MX^(hal) or the alkyl lithium reagentR¹CH₂Li can be carried out, for example, at temperature from about −100to about −20° C. In some embodiments, the reaction of the mixedtrialkoxyborane intermediate and R¹CH₂MX^(hal) is carried out at about−78° C.

The reactions of the processes described herein can be carried out inair or under an inert atmosphere. Typically, reactions containingreagents or products that are substantially reactive with air can becarried out using air-sensitive synthetic techniques that are well knownto the skilled artisan.

B. F2 Fragment

The mid-section of compounds of the present invention can be representedby fragment F2 which couples to fragment F1 by peptide bond formationfor form an F2-F1 intermediate. Methods for coupling compounds throughpeptide bonds, or amide bonds, are well known in the art and described,for example, in The Peptides: Analysis, Synthesis, Biology, Vol. I.,eds. Gross, et al., Academic Press, 1979. An example F2 fragment isprovided in Formula (E) (Pg is an amino protecting group, R² is definedherein). Additionally, protection of the amino group of amino acidsusing Boc or other amino protecting groups is well known in the art.

Compounds of Formula (E) that are amino acids or amino acid derivativesare available commercially or prepared by routine methods. For example,aza-serines can be prepared generally by the Hoffman Rearrangement(Hoffman's Reaction) using, for example, asparagine where the amide ofthe asparagine side chain is converted to an amine (which can besubsequently protected). Methods for carrying out HoffmanRearrangements, such as for amino acids, are known in the art and alsoprovided in the Examples below. Additionally aza-serines can be preparedas disclosed in Zhang, et al. J. Org. Chem., 1997, 62, 6918-6920.Boc-cyanoarginine derivatives can be prepared as disclosed in Wagenaaret al., J. Org. Chem. 1993, 58, 4331-4338. Synthesis of F2 fragmentswherein R² is —CH₂CH₂CH₂NHC(═NR⁴)NH—Y, —CH₂CONR⁵R⁶, —CH₂NHCONR⁵R⁶,—CH₂NR⁹R¹⁰, or —CH(R⁷)ZR⁸ are further disclosed herein. F2 fragments canbe obtained from commercial sources or made by methods known to oneskilled in the art.

C. F3 Fragments

A further fragment (F3) can be coupled to the F2 fragment of the F2-F1intermediate by any of various means such as by nucleophilicsubstitution or addition reactions where, for example, F2 contains anucleophile (e.g., amine) and F3 contains an electrophile (e.g., CO,SO₂, and the like) and optionally a leaving group (e.g., halo, hydroxy,alkoxy, alkylsulfonyl, arylsulfonyl, and the like). Example F3 fragmentscan have the formula R^(X)COX^(L), R^(X)SO₂X^(L), R^(X)NCO, or R^(X)HCO,(e.g., R^(X) can be R^(A), R^(B), or R^(C) as defined herein and X^(L)can be a leaving group). Coupling of R^(X)COX^(L) (such as when X^(L) isOH) to the F2-F1 intermediate can be carried out according to standardprocedures for peptide bond formation to prepare compounds having theformula F3-F2-F1 where the F3 and F2 fragments are coupled via an amidebond. In other embodiments, F3 and F2 can be coupled by a sulfonylaminolinkage prepared by reacting R^(X)SO₂X^(L) with the F2-F1 intermediatein which an amino moiety on the F2-F1 intermediate displaces the X^(L)leaving group of R^(X)SO₂X^(L). Additionally, reaction of R^(X)NCO withan amino moiety of the F2-F1 intermediate can result in a urea linkage(—HNCONH—), while reaction of R^(X)HCO with an amino moiety of the F2-F1intermediate followed by reduction of the resulting imine moiety canform an amine linkage. Other coupling means are known in the art and arealso suitable. F3 fragments can be obtained from commercial sources ormade by methods known in the art.

Certain compounds of the invention wherein R² is —(CH₂)_(d)CH(R²)NR⁹R¹⁰can be prepared by removal of an R¹⁰ amino protecting group to form thecorresponding deprotected compound wherein R¹⁰ is H. This deprotectedcompound can be reacted with a reagent having the formula R^(10a)X^(L),wherein R^(10a) has the same meaning as R¹⁰ with the exception of H andX^(L) is a leaving group such as halo or a sulfonic acid derivative, orwherein R^(10a) and X^(L) taken together represent, for example, areactive alkyl, carbocyclyl or heterocarbocyclyl isocyanate, or analkyl, carbocyclyl, heterocarbocyclyl sulphonylisocyanate. For example,the compound of Example D.26 can be prepared by the deprotection of thebenzyloxycarbonyl group of Example D.16.6 to give Example D.17, fromwhich the azaserine nitrogen can be subsequently acylated.

The present invention further provides methods for preparing azaserine(e.g., where R² is —CH₂NH₂) compounds of Formula I. In general, theazaserine group can be generated by removal of a benzyloxycarbonyl group(—C(═O)OCH₂(C₆H₅)) which is attached to one of the nitrogens of theazaserine group (e.g., compounds of Formula I where R² is —CH₂NR⁹R¹⁰ andR⁹ is H and R¹⁰ is —C(═O)OCH₂(C₆H₅)). Removal of the benzyloxycarbonylgroup can be carried out by treatment with a reducing agent, such as ahydrogenation reagent. In some embodiments, the hydrogenation reagentcontains H₂ which is optionally used in the presence of a metal catalyst(e.g., Pd/C 10%). Hydrogenation can be further carried out in thepresence of a protic acid such as HCl and in a suitable hydrogenationsolvent containing, for example, an alcohol and/or an ether solvent. Insome embodiments, the hydrogenation solvent contains an ether such as1,4-dioxane. In further embodiments, the hydrogenation solvent cotainsan alcohol such as methanol. In further embodiments, the hydrogenationsolvent contains a mixture of alcohol and ether. An example preparationof an azaserine compound according to this process is provided, forexample, in Example D.17. Reaction parameters including temperature,pressure, atmosphere and the like are readily determined by one skilledin the art of chemical synthesis and reaction progress can be monitoredby routine methods including, e.g., NMR.

Accordingly, the present invention provides a process for thepreparation of compounds of Formula (I):

wherein:

-   R¹ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, or C₃-C₇    cycloalkyl;-   R² is —CH₂NH₂;-   Q is —B(OR¹⁴)₂, or a cyclic boronic ester wherein said cyclic    boronic ester contains from 2 to 20 carbon atoms, and, optionally, a    heteroatom which can be N, S, or O;-   R¹⁴ is C₁-C₄ alkyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl;-   X is R^(A)C(═O)—;-   R^(A) is C₁-C₂₀ alkyl optionally substituted with R²⁰; C₂-C₂₀    alkenyl optionally substituted with R²⁰; C₂-C₂₀ alkynyl optionally    substituted with R²⁰; carbocyclyl optionally substituted with 1-5    R²¹; or heterocarbocyclyl optionally substituted with 1-5 R²¹;-   R²⁰ is selected from the group consisting of:    -   —CN, halo, haloalkyl-, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄        alkynyl, —CO₂H, —C(═O)CO₂H, —C(═O)NH₂, —C(═O)H, —S(═O)NH₂,        —S(═O)₂NH₂, —OH, —SH, —NH₂, —NH(alkyl), —N(alkyl)₂, —NHC(═O)NH₂,        —NHC(═O)R^(20a), —NHC(═O)OR^(20a), —OR^(20a), —SR^(20a),        —S(═O)R^(20a), —S(═O)₂R^(20a), —S(═O)₂—NHR^(20a),        —SC(═O)R^(20a), —C(═O)R^(20a), —C(═O)NHR^(20a), —C(═O)O—R^(20a),        —NHS(═O)₂R^(20a), —NHR^(20b), phthalimido, —(O-alkyl)_(r),        —O-alkyl-OH, —(O-alkyl)_(r)-OH, —OR^(20c), —SR^(20c),        —O-alkyl-R^(20c), —S-alkyl-R^(20c), —S(═O)—R^(20c),        —S(═O)₂—R^(20c), —S(═O)₂—NHR^(20c), —SC(═O)R^(20c),        —C(═O)R^(20c), —C(═O)OR^(20c), C(═O)NHR^(20c), carbocyclyl        optionally substituted with 1-5 R²¹; and heterocarbocyclyl        optionally substituted with 1-5 R²¹;-   R^(20a) is C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, or C₂-C₂₀ alkynyl; wherein    said alkyl, alkenyl, or alkynyl is optionally substituted by one or    more halo, C₁-C₄ alkyl, aryl, heteroaryl or —NHR^(20b);-   R^(20b) is an amino protecting group;-   R^(20c) is carbocyclyl optionally substituted with 1-5 R²²; or    heterocarbocyclyl optionally substituted with 1-5 R²²;-   R²¹ is selected from the group consisting of:    -   C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, C₁-C₂₀ alkoxy,        C₁-C₂₀ thialkoxy, —OH—CN, halo, haloalkyl, —NH₂, —NH(alkyl),        —N(alkyl)₂, —NHC(═O)O-alkyl, —NHC(═O)alkyl, —C(═O)O-alkyl,        —C(═O)alkyl, —S(═O)-alkyl, —S(═O)₂-alkyl, —S(═O)-aryl,        —S(═O)₂-aryl, carbocyclyl optionally substituted with 1-5 R²²,        and heterocarbocyclyl optionally substituted with 1-5 R²²;-   R²² is selected from the group consisting of:    -   C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, phenyl, halo,        haloalkyl, alkoxy, thialkoxy, amino, alkylamino, dialkylamino,        carboxyl, alkyl-OC(═O)—, alkyl-C(═O)—, aryl-OC(═O)—,        alkyl-OC(═O)NH—, aryl-OC(═O)NH—, alkyl-C(═O)NH—, alkyl-C(═O)O—,        (alkyl-O)_(r)-alkyl, HO-(alkyl-O)_(r)-alkyl-, —OH, —SH, —CN,        —N₃, —CNO, —CNS, alkyl-S(═O)—, alkyl-S(═O)₂—, H₂NS(═O)—, and        H₂NS(═O)₂—; and-   r is 2, 3, 4, or 5;    comprising:    reacting a compound of Formula (I) wherein R² is    —CH₂NH—C(═O)OCH₂(C₆H₅); with a suitable hydrogenation reagent for a    time and under conditions suitable for forming the compound of    Formula (I) wherein R² is —CH₂NH₂, provided the hydrogenation agent    is selective for the benzyloxycarbonyl group of R².

In some embodiments, the hydrogenation agent is H₂ in the presence ofPd/C 10% and HCl in 1,4-dioxane.

Boronic Ester/Boronic Acid Conversion

Compounds of the invention containing boronic esters, such as pinanediolesters, can be hydrolyzed by any suitable means to prepare correspondingboronic acid (—B(OH)₂) derivatives. Hydrolysis conditions can includecontacting a boronic ester with excess acid, such as a protic acid likeHCl.

Conversely, boronic acids can be esterified by contacting the acidcompound (—B(OH)₂) with an alcohol such as a diol for sufficient time toproduce the corresponding ester. The esterification reaction can be acidor base catalyzed.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of noncriticalparameters which can be changed or modified to yield essentially thesame results.

EXAMPLES Example A.1 Synthesis of(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutylaminehydrochloride Salt Step 1:2-(2-methylpropyl)-(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborole

A mixture of (+)-pinanediol (23.9 g, 0.140 mol) and2-methylpropylboronic acid (15 g, 0.147 mol) in diethyl ether (300 ml)was stirred at room temperature for 24 h. The mixture was dried overanhydrous sodium sulfate and purified by column chromatography (Silicagel 230-400 mesh), eluting with hexane:ethyl acetate 90:10 mixture. Theproduct was obtained as a clear oil (32.6 g, 94% yield).

¹H NMR (DMSO-d₆): 4.28 (1H, dd, J=8.8 Hz, 2.0); 2.30 (1H, m); 2.18 (1H,m); 1.96 (1H, t, J=5.3); 1.86 (1H, m); 1.78 (1H, set, J=6.8); 1.68 (1H,m); 1.30 (3H, s); 1.25 (3H, s); 1.01 (1H, d); 0.9 (6H, d, J=6.6); 0.81(3H, s); 0.69 (2H, m).

Step 2:2-[(1S)-1-chloro-3-methylbutyl]-(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborole

A solution of lithium diisopropylamide was prepared by addition of 10.0M butyl lithium solution in hexane (25.4 ml, 0.254 mol) to a solution ofdiisopropylamine (35.7 ml, 0.254 mol) in dry tetrahydrofuran (60 ml), at−50° C., and allowing the temperature to rise to −30° C. This solutionwas transferred via canula into a solution of2-(2-methylpropyl)-(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaboroleof Step 1 (50 g, 0.212 mol) and CH₂Cl₂ (50 ml, 0.848 mol) in drytetrahydrofuran (700 ml), while keeping the temperature below −70° C. A1.0 M solution of dry zinc chloride in diethyl ether (339 ml, 0.339 mol)was then added over a 30 minutes period while keeping the internaltemperature below −70° C. The reaction mixture was stirred at −78° C.for 3 hours, then allowed to warm to room temperature. After removal ofthe solvents by rotary evaporation the residue was partitioned betweenpetroleum ether (1000 ml) and a 10% aqueous solution of ammoniumchloride (800 ml). The aqueous layer was further extracted withpetroleum ether (300 ml). The combined organic phases were dried overanhydrous sodium sulfate and concentrated. The product was obtained as abrown oil (59.0 g, 98% yield) containing about 9% mol/mol of startingmaterial (¹H-NMR), and was used in the subsequent step without furtherpurification.

¹H NMR (DMSO-d₆): 4.43 (1H, dd, J=8.8, 1.8); 3.59 (1H, m); 2.33 (1H, m);2.21 (1H, m); 2.01 (1H, m); 1.88 (1H, m); 1.84-1.55 (5H, m); 1.34 (3H,s); 1.26 (3H, s); 1.09 (1H, J=10.1); 0.9 (3H, d, J=6.8); 0.87 (3H, d,J=6.4); 0.82 (3H, s).

Step 3:N,N-Bis(trimethylsilyl)-(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutylamine

A 1.0 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran(189 ml, 0.189 mol) was added, over 30 minutes, to a solution of crude2-[(1S)-1-chloro-3-methylbutyl]-(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaboroleof Step 2 (59.0 g, 91% purity, 0.189 mol) in tetrahydrofuran (580 ml)while cooling at −78° C. The reaction mixture was allowed to slowly warmto room temperature overnight. The solvent was removed by rotaryevaporation and the residue taken up with dry hexane (800 ml). Theresulting suspension was stirred at room temperature for 2 hours, thenthe solid was removed by filtration on a celite cake, which was washedwith dry hexane (3×100 ml). The filtrate was concentrated giving asatisfactorily pure product as a brown oil (79 g) in practicallyquantitative yield. The product was used for the subsequent step withoutfurther purification.

¹H NMR (DMSO-d₆): 4.33 (1H, dd, J=1.5 Hz, 8.6); 2.58 (1H, m); 2.29 (1H,m); 2.18 (1H, m); 1.95 (1H, t, J=5.9); 1.85 (1H, m); 1.9-1.55 (3H, m);1.31 (3H, s); 1.24 (3H, s); 1.17 (1H, m); 1.01 (1H, d, J=10.6); 0.85(3H, d, J=6.6), 0.83 (3H, d, J=6.6); 0.80 (3H, s); 0.08 (18H, s).

Step 4:(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutylamineHydrochloride Salt

To a solution of crudeN,N-Bis(trimethylsilyl)-(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutylamineof Step 3 (79 g, 0.193 mol) in a mixture of dioxane (100 ml) and diethylether (200 ml), a 4 N solution of hydrogen chloride in dioxane (193 ml,0.772 mol) was added, while cooling at 0° C. The mixture was thenstirred at room temperature for 4 hours and concentrated. The residuewas taken up with anhydrous hexane (500 ml) and a 2 M solution ofhydrogen chloride in diethyl ether (48 ml, 0.096 mol) was added. Themixture was stirred at 0° C. for 1 hour, then concentrated. The residuewas taken up with anhydrous hexane and the resulting suspension wasstirred at room temperature overnight. The solid was collected byfiltration and dried under vacuum affording 38.1 g of product (66%yield). A second crop (4.13 g, 7% yield) was obtained from the motherliquors.

¹H NMR (DMSO-d₆): 7.85 (3H, br); 4.45 (1H, dd, J=9.2 Hz); 2.78 (1H, m);2.34 (1H, m); 2.21 (1H, m); 2.01 (1H, t, J=5.3); 1.89 (1H, m); 1.82-1.65(2H, m); 1.49 (1H, m); 1.38 (3H, s); 1.27 (3H, s); 1.12 (1H, d, J=1.12);0.87 (6H, d, J=6.6); 0.83 (3H, s).

Example A.2 Alternate synthesis of2-(2-methylpropyl)-(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaboroleStep 1:2-(1-methylethoxy)-(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborole

To a solution of (1S,2S,3R,5S)-(+)-Pinanediol (50.0 g, 0.293 mol) inanhydrous tetrahydrofuran (350 ml) triisopropoxy borane was slowly addedwhile stirring at 0° C. under nitrogen. After 2 h the solvent wasremoved by rotary evaporation. The oily residue was redissolved inhexane (150 ml) and the solution was filtered to remove a very smallamount of a white solid. The filtrate was concentrated by rotaryevaporation affording the product as a clear oil (62.6 g, 90% yield).

¹H NMR (DMSO-d₆): 4.31-4.20 (2H, m); 2.34-2.16 (2H, m); 1.96 (1H, t,J=5.5); 1.90-1.85 (1H, m); 1.74-1.67 (1H, m); 1.32 (3H, s); 1.31 (1H, d,J=7.6); 1.25 (3H, s); 1.14 (3H, d, J=6.1); 1.13 (3H, d, J=6.1); 0.81(3H, s).

Step 2:2-(2-Methylpropyl)-(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborole

A 2M solution of isobutyl magnesium bromide in diethyl ether (131.5 ml,0.263 mol) was added dropwise, in 1 hour, to a solution of2-(1-methylethoxy)-(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaboroleobtained in Step 1 (62.6 g, 0.263 mol), in anhydrous tetrahydrofuran(330 ml) while stirring at −78° C., under nitrogen. The mixture was thenallowed to warm to room temperature, then transferred in a mixture of 2Nsulfuric acid (150 ml) and diisopropyl ether (250 ml). After stirringfor 10 minutes, a saturated solution of NaCl was added (100 ml) and thelayers were separated. The organic phase was washed with brine (100 ml),dried over sodium sulfate and concentrated. The residue was purified bycolumn chromatography (silica gel) eluting with 5% diethyl ether inhexane. The product was obtained as a clear oil (38.45 g, 62% yield).

Example B.1 Carbamic acid 1,1-Dimethylethyl Ester,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl]

Method A: HOAt/HATU

To a solution of BocNH(NO₂)ArgOH (15.7 g, 49.3 mmol) in anhydrous DMF(100 ml), HATU (O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate; 18.7 g, 49.3 mmol) and HOAt(1-hydroxy-7-azabenzotriazole; 6.71 g, 49.3 mmol) were added. Themixture was cooled to 0° C. and N-methylmorpholine was added (13.6 ml,0.123 mol). After 10 minutes(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutylaminehydrochloride salt of Example A.1 (12.4 g, 41.1 mmol) was added. Thecooling bath was removed and the mixture was stirred at r.t. for 4.5hours. The mixture was diluted with ethyl acetate (800 ml), washed witha 2% solution of citric acid (2×150 ml), 2% solution of NaHCO₃ (2×150ml) and 2% solution of NaCl (2×150 ml). The aqueous phases were furtherextracted with ethyl acetate (150 ml). The combined organic phases weredried over sodium sulfate and concentrated. The resulting oily residuewas redissolved in ethyl acetate (500 ml) and the solution was washedwith cold water (200 ml). The aqueous phases were further extracted withethyl acetate (500 ml). The combined organic phases were dried oversodium sulfate and concentrated. The residue was dissolved in diethylether (100 ml) an the solution was slowly added to hexane (600 ml) whilestirring. The white solid was collected by filtration (43.4 g) andpurified by column chromatography eluting initially with 50:50hexane:ethyl acetate mixture and then with ethyl acetate. The fractionscontaining the product were concentrated, the residue was dissolved indiethyl ether (100 ml) and the resulting solution was slowly added tohexane (600 ml) while stirring. The white solid was collected byfiltration (15.2 g, 66% yield).

Method B: IBCF

To a suspension of BocNH(NO₂)ArgOH (5.82 g, 18.2 mmol) in anhydrousdichloromethane (100 ml) N-methylmorpholine (2.0 ml, 18.2 mmol) wasadded. The mixture was cooled to −15° C. then isobutyl chloroformate wasadded (2.37 ml, 18.2 mmol). The mixture was stirred at −15° C. for 10minutes then(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutylaminehydrochloride salt obtained as in Example A.1 was added (5.0 g, 16.6mmol), immediately followed by further N-methylmorpholine (2.0 ml, 18.2mmol). The reaction mixture was stirred for 1.5 hours at −15° C., thenallowed to warm to room temperature and partitioned between ethylacetate (150 ml), water (150 ml) and 0.1N hydrochloric acid (10 ml). Theorganic phase was washed with a saturated solution of NaHCO₃, dried overanhydrous sodium sulphate and concentrated. The oily residue (9.25 g)was purified by crystallization from ethyl acetate affording three cropsof satisfactorily pure product (5.03 g, 54% yield).

¹H NMR (DMSO-d₆): 8.80 (1H, br); 8.50 (1H, br), 7.87 (2H, br); 7.01 (1H,d, J=7.9), 4.07 (1H, dd, J=7.9); 4.0 (1H, m); 3.12 (2H, m); 2.55 (1H,m); 2.2 (1H, m); 2.01 (1H, m); 1.83 (1H, t, J=5.1); 1.78 (1H, m);1.74-1.44 (7H, m); 1.38 (9H, s); 1.33 (1H, d, J=10.3); 1.24 (5H, s);1.22 (3H, s); 0.84 (6H, d, J=6.6); 0.81 (3H, s)

Example B.2 Carbamic acid 1,1-Dimethylethyl Ester,N-[1(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]-

Boc-L-threonine (870 mg, 3.97 mmol, 1.2 eq.) was dissolved in DMF dry(30 ml) at r.t. To this solution, TBTU(N,N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate;1270 mg, 3.97 mmol, 1.2 eq.) was added and the mixture was cooled at0°-5° C. Then NMM (0.9 ml, 8.27 mmol, 2.5 eq.) and(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutylaminehydrochloride salt of Example A.1 (1000 mg, 3.3 mmol, 1 eq.) were added.The mixture was stirred at r.t. for 16 h, then was extracted with ethylacetate (100 ml) washed with the following solutions: citric acid 2% (50ml), sodium bicarbonate 2% (50 ml), NaCl 2% (50 ml). The organicsolution was dried over sodium sulphate anhydrous, filtered andevaporated under reduced pressure to give 1290 mg of glassy solid. Yield84.3%. M.p. 25°-30° C.

¹H NMR (DMSO-d₆): 8.88 (1H, br); 6.49 (1H, d, J=8.4 Hz); 4.88 (1H, d,J=5.8); 4.05 (1H, dd); 3.93 (1H, m); (1H, m); 2.51 (1H, m); 2.19 (1H,m); 2.01 (1H, m); 1.83 (1H, t, J=5.9), 1.78 (1H, m); 1.68 (1H, m); 1.62(1H, m); 1.39 (9H, s); 1.34 (1H, d, J=10.0); 1.24 (3H, s); 1.22 (3H, s);1.06 (3H, d, J=6.4); 0.85 (6H, d, J=6.4); 0.80 (3H, s)

Example B.3 Further Intermediate Compounds

Starting from the appropriate intermediate and following either of theprocedures described in the Example B.1 and B.2, the intermediatesreported below were prepared.

(2S)-2-[(1,1-Dimethylethoxycarbonyl)amino]-5-ureidopentanamide,N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]

¹H NMR (DMSO-d₆): 8.85 (1H, br); 7.01 (1H, d, J=8.0 Hz); 5.9 (1H, t,J=5.7); 5.36 (2H, br); 4.03 (2H, m); 2.93 (2H, m); 2.19 (1H, m); 2.0(1H, m); 1.83 (1H, t, J=5.3); 1.78 (1H, m); 1.68 (1H, m); 1.62 (1H, m);1.52 (2H, m); 1.38 (9H, s); 1.33 (1H, d, J=9.9); 1.24 (3H, s); 1.22 (2H,s); 0.86 (3H, d, J=6.6); 0.84 (3H, d, J=6.6); 0.80 (3H, s).

(2S)-3-(Aminocarbonyl)-2-[(1,1-dimethylethoxycarbonyl)amino]propanamide,N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]

¹H NMR (DMSO-d₆): 8.74 (1H, br); 7.28 (1H, br); 6.95 (2H, m); 4.36 (1H,m); 4.07 (1H, m); 2.55 (1H, m); 2.38 (2H, m); 2.2 (1H, m); 2.02 (2H, m);1.84 (1H, t, J=5.5); (1H, m); 1.79 (1H, m); 1.68 (1H, m); 1.63 (1H, m);1.38 (9H, s); 1.33 (1H, d, J=10); 1.24 (3H, s); 1.22 (2H, s); 0.85 (3H,d, J=6.4); 0.83 (3H, d, J=6.4); 0.81 (3H, s).

Carbamic acid benzyl ester,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl].

M.p. 57-60° C. ¹H NMR (DMSO-d6): 8.66 (1H, s); 7.40-7.29 (5H, m); 7.09(1H, d, J=8.75); 5.06 (2H, s); 4.90 (1H, J=5.68); 4.11-3.99 (2H, m);3.91-3.77 (1H, m); 2.58-2.53 (1H, m); 2.26-2.14 (1H, m); 2.07-1.97 (1H,s); 1.84 (1H, t, J=5.52); 1.81-1.75 (1H, m); 1.73-1.58 (2H, m); 1.33(2H, d, J=10.1); 1.27-1.20 (7H, m); 1.06 (3H, t, J=6.27); 0.91-0.79 (9H,m).

Example B.4(2S)-2-[(1,1-Dimethylethoxycarbonyl)amino]-3-[(4-methylbenzoyl)amino]propanamide,N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]-

(2S)-2-[(1,1-Dimethylethoxycarbonyl)amino]-3-[(4-methylbenzoyl)amino]-propanoicacid, (650 mg, 2 mmol, 1.2 eq.) of Example G.6, was dissolved in DMF dry(15 ml), under nitrogen, and TBTU (640 mg, 2 mmol, 1.2 eq.) was added atr.t. The mixture was cooled at 0°-5° C. with ice bath and NMM (0.55 ml,5 mmol, 2.5 eq.) and(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutylaminehydrochloride salt, (500 mg, 1.65 mmol, 1 eq.) of Example A.1, wereadded. The mixture was stirred overnight, poured in water (200 ml) andextracted with ethyl acetate (100 ml). The organic layer was washed withthe following solutions: citric acid 2% (20 mL), sodium bicarbonate 2%(20 ml), NaCl 2% (20 ml). The organic solution was dried over sodiumsulphate anhydrous, filtered and evaporated to give 740 mg of glassysolid (quantitative yield).

¹H NMR (DMSO-d₆) 8.76 (1H, br); 8.28 (1H, t, J=5.31 Hz); 7.71 (2H, d,J=7.9); 7.26 (2H, d, J=7.9); 6.97 (1H, d, J=8.0); 4.27 (1H, m); 4.07(1H, dd, J=8.2, 1.5); 3.48 (2H, m), 2.58 (1H, m); 2.35 (3H, s); 2.19(1H, m); 2.02 (1H, m); 1.83 (1H, t, J=4.9); 1.78 (1H, m); 1.62 (2H, m);1.35 (12H, m); 1.24 (3H, s); 1.23 (3H, s); 0.82 (3H, d); 0.80 (3H, d);0.78 (3H, s).

Example B.52-S-[(1,1-Dimethylethoxycarbonyl)amino]-3-(hexanoylamino)-propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]

2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(hexanoylamino)propionic acid,(300 mg, 1 mmol, 1.2 eq.) of Example G.7 was dissolved in DMF dry (25ml), under nitrogen, and TBTU (318 mg, 1 mmol, 1.2 eq.) was added atr.t. The mixture was cooled at 0°-5° C. with ice bath and NMM (0.27 ml,2.47 mmol, 2.47 eq.) and(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutylaminehydrochloride salt, (250 mg, 0.82 mmol, 1 eq.) of Example A.1, wereadded. The mixture was stirred 3 h, poured in water (150 ml) andextracted with ethyl acetate (100 ml). The organic layer was washed withthe following solutions: citric acid 2% (50 mL), sodium bicarbonate 2%(50 ml), NaCl 2% (50 ml). The organic solution was dried over sodiumsulphate anhydrous, filtered and evaporated to give 450 mg of glassysolid. Yield quantitative.

Analytical data:

¹H NMR (DMSO-d₆).

δ_(H): 8.71 (1H, br d, J=2.6 Hz); 7.73 (1H, br t, J=5.9 Hz); 6.81 (1H,d, J=8.2); 4.10 (2H, m); 3.24 (2H, m); 2.56 (1H, m); 2.19 (1H, m); 2.03(3H, m); 1.83 (1H, t, J=5.5); 1.78 (1H, m); 1.64 (2H, m); 1.47 (2H, m);1.36 (9H, s); 1.4-1.15 (9H, m); 1.24 (3H, s); 1.21 (3H); 0.83 (9H, m);0.79 (3H, s)

Example B.62-S-[(1,1-Dimethylethoxycarbonyl)amino]-3-(4-fluorosulfonylamino)propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]

2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(4-fluorosulfonylamino)propionicacid, (1.39 g, 3.83 mmol, 1.2 eq.) of Example G.8, was dissolved in DMFdry (20 ml), under nitrogen, and TBTU (1.23 g, 3.83 mmol, 1.2 eq.) wasadded at r.t. The mixture was cooled at 0°-5° C. with ice bath and NMM(1 ml, 9.57 mmol, 3 eq.) and(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutylaminehydrochloride salt, (0.96 g, 3.19 mmol, 1 eq.) of Example A.1, wereadded. The mixture was stirred 2 h, poured in water (200 ml) andextracted with ethyl acetate (100 ml). The organic layer was washed withthe following solutions: citric acid 2% (50 mL), sodium bicarbonate 2%(50 ml), NaCl 2% (50 ml). The organic solution was dried over sodiumsulphate anhydrous, filtered and evaporated with diethyl ether to give1.5 g of white solid. Yield 77%.

Analytical data:

¹H NMR (DMSO-d₆).

δ_(H): 8.54 (1H, d, J=2.9 Hz); 7.91 (2H, m); 7.75 (1H, t, J=5.9); 7.50(2H, t, J=8.8); 6.83 (1H, d, J=8.4); 4.19 (1H, br d, J=8.2); 4.14 (1H,m); 3.01 (2H, m); 2.69 (1H, m); 2.25 (1H, m); 2.09 (1H, m); 1.90 (1H, t,J=5.7); 1.85 (1H, m); 1.8-1.6 (2H, m); 1.5-1.2 (5H, m); 1.43 (9H, s);1.29 (6H, s); 0.89 (6H, d, J=6.4); 0.86 (3H, s).

Example B.72-S-[(1,1-Dimethylethoxycarbonyl)amino]-3-(3,4-dimethoxyphenylacetamido)propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]

2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(3,4-dimethoxyphenylacetamido)-propionicacid, (0.73 g, 1.90 mmol, 1.2 eq.) of Example G.9, was dissolved in DMFdry (20 ml), under nitrogen, and TBTU (0.61 g, 1.90 mmol, 1.2 eq.) wasadded at r.t. The mixture was cooled at 0°-5° C. with ice bath and NMM(0.52 ml, 4.7 mmol, 2.5 eq.) and(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutylaminehydrochloride salt, (0.47 g, 1.6 mmol, 1 eq.) of Example A.1, wereadded. The mixture was stirred 2 h, poured in water (200 ml) andextracted with ethyl acetate (100 ml). The organic layer was washed withthe following solutions: citric acid 2% (50 mL), sodium bicarbonate 2%(50 ml), NaCl 2% (50 ml). The organic solution was dried over sodiumsulphate anhydrous, filtered and evaporated with diethyl ether to give0.95 g of crude that was purified by silica gel chromatography (eluentethyl acetate) to give 0.3 g of white foam. Yield 30%.

Analytical data: TLC silica gel (eluent ethyl acetate 100%, R.f.=0.50)

¹H NMR (DMSO-d₆).

δ_(H): 8.69 (1H, d, J=2.6 Hz); 7.90 (1H, t, J=5.7); 6.85 (2H, m); 6.74(1H, dd, J=1.5, 8.1); 6.85 (3H, m); 4.12 (2H, m); 3.73 (3H, s); 3.72(3H, s); 3.34 (2H, s); 3.31 (2H, m); 2.58 (1H, m); 2.20 (1H, m); 2.03(1H, m); 1.85 (1H, t, J=5.3); 1.79 (1H, m); 1.66 (2H, m); 1.38 (9H, s);1.40-1.15 (3H, m); 1.25 (3H, s); 1.23 (3H, s); 0.83 (6H, d, J=6.6); 0.81(3H, s).

Example B.82-S-[(1,1-Dimethylethoxycarbonyl)amino]-3-(3-phenylureido)propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]

2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(3-phenylureido)propionicacid, (0.41 g, 1.26 mmol, 1.2 eq.) of Example G.10, was dissolved in DMFdry (20 ml), under nitrogen, and TBTU (0.40 g, 1.26 mmol, 1.2 eq.) wasadded at r.t. The mixture was cooled at 0°-5° C. with ice bath and NMM(0.346 ml, 3.15 mmol, 2.5 eq.) and(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutylaminehydrochloride salt, (0.31 g, 1 mmol, 1 eq.) of Example A.1, were added.The mixture was stirred 2 h, poured in water (200 ml) and extracted withethyl acetate (100 ml). The organic layer was washed with the followingsolutions: citric acid 2% (50 mL), sodium bicarbonate 2% (50 ml), NaCl2% (50 ml). The organic solution was dried over sodium sulphateanhydrous, filtered and evaporated with diethyl ether (50 ml) to give0.58 g of white solid. Yield 96.6%.

Analytical data: TLC silica gel (eluent ethyl acetate 100%, R.f.=0.47),m.p. 128°-130° C.

¹H NMR (DMSO-d₆).

δ_(H): 8.79 (1H, d, J=2.7 Hz); 8.69 (1H, s); 7.38 (2H, d, J=7.9); 7.22(2H, t, J=8.1); 7.00 (1H, d, J=8.1); 6.90 (1H, t, J=7.3); 6.16 (1H, t,J=5.7); 4.12 (2H, m); 3.45 (1H, m); 3.17 (1H, m); 2.60 (1H, m); 2.21(1H, m); 2.04 (1H, m); 1.85 (1H, t, J=5.3); 1.79 (1H, m); 1.66 (2H, m);1.38 (9H, s); 1.40-1.15 (3H, m); 1.26 (3H, s); 1.23 (3H, s); 0.84 (6H,d, J=6.6); 0.81 (3H, s).

Example B.9 Synthesis of Further Compounds

Following the procedures of Examples B.4-B.8, the following compoundscan be prepared by reaction of(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutylaminehydrochloride salt of Example A.1 and intermediates of Examples G.11,G.12 and G.13.

B.9.1 2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(acetamido-)propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl].

B.9.2 2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(9-fluorenylmethyloxycarbamoyl)ethyl]-propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl].

B.9.3 2-S-[(1,1-dimethylethoxycarbonyl)amino]-2-[(pentylureido)ethyl]-N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-

B.9.4 2-S-[(1,1-dimethylethoxycarbonyl)amino]-2-(methanesolfonamido)ethyl]-N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-

B.9.5 2-S-[(1,1-dimethylethoxycarbonyl)amino]-2-[(ethoxycarbonylsuccinyl]-amide)ethyl]-N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-

B.9.6 2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(benzyloxycarbamoyl)ethyl]-propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-mediano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl].

B.9.7 2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-[2-(1H-pyrazol)ethyl]-N-[(1S)-1-[[[(1R)-1-[(3aS,aS,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl-]-3-methylbutyl]amino]carbonyl]

Example B.10 Carbamic acid 1,1-Dimethylethyl ester,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-1-methylbutyl]amino]carbonyl]-methyl

This compound has been prepared following the procedure of Example B.1Method B starting from(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutylaminehydrochloride salt of Example A.1 and commercially availableN-(1,1-dimethylethoxycarbonyl)glycine.

¹H-NMR (DMSO-d6): 8.84 (1H, s); 7.08 (1H, t, J=5.93 Hz); 4.06 (1H, d,J=7.48 Hz); 3.67 (2H, t, J=5.32 Hz); 2.60-2.48 (1H, m); 2.24-2.16 (1H,m); 2.06-1.96 (1H, m); 1.84 (1H, t, J=5.50 Hz); 1.82-1.76 (1H, m);1.74-1.58 (2H, m); 1.39 (10H, bs); 1.23 (9H, d, J=8.18 Hz); 0.87-0.83(6H, m); 0.82 (3H, bs).

Example C.1 (2S)-2-amino-5-[[imino(nitroamino)methyl]amino]pentanamide,N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl];Hydrochloride Salt

Method A

A 4 N solution of hydrogen chloride in dioxane (15 ml) was added to asolution of carbamic acid 1,1-dimethylethyl ester,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl]-of Example B.1, (4.04 g, 7.06 mmol) in a mixture of dioxane (40 ml) anddiethyl ether (7 ml), while cooling at 0° C. The reaction mixture wasallowed to warm to room temperature and stirred for further 4 hours. Thesolvent was removed by rotary evaporation, the residue was treated withdiethyl ether (50 ml) and the mixture was stirred at r.t. for threedays. The resulting solid was collected by filtration affording 3.18 gof pure product (90% yield)

Method B

Carbamic acid 1,1-dimethylethyl ester,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]-amino]-carbonyl]-4-[[imino(nitroamino)-methyl]-amino]butyl]-of Example B.1, (3 g, 5.3 mmol) was dissolved in Et₂O (40 mL) and asolution of about 10% HCl in Et₂O (20 mL) was added dropwise at 0° C.under nitrogen. The reaction mixture was allowed to warm to roomtemperature and to stir for further 5 hours. The solvent was decantedand the residue, washed twice with Et₂O (20 mL), was dried in vacuo togive the title compound as a white powder (2.43 g, yield 91%).

¹H NMR (DMSO-d₆): 8.56 (2H, br); 8.22 (3H, br); 7.97 (2H, br); 4.28 (1H,dd, J=8.6 Hz, 2.01); 3.77 (1H, m); 3.04 (1H, m); 2.28 (1H, m); 2.11 (2H,m), 1.92 (1H, t, J=5.5); 1.83 (1H, m); 1.79-1.59 (4H, m); 1.59-1.37 (3H,m); 1.31 (4H, s); 1.24 (3H, s); 1.19 (1H, d, J=10.4); 0.88 (3H, d,J=6.0); 0.86 (3H, d, J=6.0); 0.81 (3H, s).

Example C.2 Boronic acid,[(1R)-1-[[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]amino]-3-methylbutyl],Hydrochloride Salt

Carbamic acid 1,1-dimethylethyl ester,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl]-of Example B.1, (3.1 g, 5.48 mmol) was carefully dissolved, undernitrogen at 0° C., in 20 mL of HCl 37%; the resultant mixture wasallowed to warm to room temperature and to stir overnight. The reactionmixture was washed with Et₂O until complete removal of pinanediol; theaqueous solution was concentrated to dryness and dried in vacuo toafford 1.82 g (4.93 mmol, yield 90%) of the title compound, used withoutfurther purification.

¹H NMR (DMSO+D₂O+TFA): 3.78 (m, 1H); 3.19 (m, 2H); 3.09 (m, 1H); 1.71(m, 2H); 1.70-1.48 (m, 3H); 1.49-1.23 (m, 2H); 0.89 (d, J=5.8 Hz, 3H);0.88 (d, J=5.8 Hz, 3H).

Example C.3 Synthesis of Further Intermediates

Starting from the appropriate intermediate and following either theprocedures described in the Example C.1 the intermediates reported belowwere prepared:

(2S,3R)-2-Amino-3-hydroxybutanamide,N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]-,Hydrochloride Salt

¹H NMR (DMSO-d₆) δ_(H): 8.62 (1H, d, J=5.0 Hz); 8.17 (3H, d, J=3.5);4.28 (1H, dd, J=8.8, 1.8); 3.78 (1H, m); 3.52 (1H, m); 3.00 (1H, m);2.28 (1H, m); 2.10 (1H, m); 1.92 (1H, t, J=5.7); 1.84 (1H, m); 1.75-1.62(2H, m); 1.43 (1H, m); 1.31 (3H, s); 1.25 (3H, s); 1.22 (1H, d, J=10.6);1.14 (3H, d, J=6.2); 0.88 (3H, d, J=6.4); 0.86 (3H, d, J=6.4); 0.81 (3H,s)

(2S)-2-Amino-5-ureidopentanamide,N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl];hydrochloride salt

¹H NMR (DMSO-d₆) 8.51 (1H, d, J=5.1 Hz); 8.17 (3H, br); 6.1 (1H, br);4.27 (1H, dd, J=8.6 Hz, 1.8); 3.73 (1H, m); 2.99 (1H, m); 2.94 (2H, t);2.27 (1H, m); 2.10 (1H, m), 1.92 (1H, t, J=5.5); 1.82 (1H, m); 1.75-1.15(9H, m); 1.30 (3H, s); 1.23 (3H, m); 0.87 (3H, d, J=6.0); 0.85 (3H, d,J=6.0); 0.80 (3H, s).

(2S)-2-Amino-3-carbamoylpropanamide,N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl];Hydrochloride Salt

¹H-NMR (DMSO-d6): 8.46-8.41 (1H, m); 8.06 (3H, bs); 7.67 (1H, s); 7.26(1H, s); 4.30-4.25 (1H, m); 4.08-4.02 (1H, m); 2.96 (1H, m); 2.60-2.52(1H, m); 2.36-2.24 (1H, m); 2.20-2.10 (1H, m); 1.95 (1H, t, J=5.5);1.88-1.83 (1H, m); 1.75-1.60 (2H, m); 1.46-1.36 (1H, m); 1.32 (3H, s);1.30-1.18 (6H, m); 0.86 (6H, t, J=6.7); 0.82 (3H, s).

2-Aminoacetamide,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-1-methylbutyl];Hydrochloride salt

¹H-NMR (DMSO-d6): 8.50 (1H, s); 8.20 (3H, bs); 4.29 (1H, d, J=7.70 Hz);3.15 (2H, bs); 3.05 (1H, s); 2.36-2.24 (1H, m); 2.20-2.10 (1H, m); 1.95(1H, t, J=5.38 Hz); 1.85 (1H, s); 1.75-1.60 (2H, m); 1.50-1.38 (1H, m);1.35-1.30 (3H, m); 1.28-1.25 (4H, m); 1.24-1.17 (1H, m); 0.86 (6H, t,J=5.94 Hz); 0.84 (3H, s).

Example C.4 (2S)-2-Amino-3-[(4-methylbenzoyl)amino]propanamide,N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]-,Hydrochloride Salt

(2S)-2-[(1,1-Dimethylethoxycarbonyl)amino]-3-[(4-methylbenzoyl)-amino]-propanamide,N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]-,Example B.4, (740 mg, 1.65 mmol, 1 eq.), was dissolved in 1,4-dioxane(20 ml). To this solution, HCl 4N in 1,4-dioxane (5 ml, 19.8 mmol, 12eq.) was added and the solution stirred overnight at r.t. The solventwas removed under reduced pressure to give 800 mg of a glassy solid(quantitative yield).

¹H NMR (DMSO-d₆) 8.63 (1H, d, J=5.5 Hz); 8.38 (1H, t, J=8.4 Hz); 8.34(3H, br); 7.80 (2H, t, J=8.2); 7.28 (2H, d, J=8.2 Hz); 4.15 (1H, dd,J=8.8, 1.8); 4.02 (1H, br); 3.66 (1H, m); 3.55 (1H, m); 2.99 (1H, m);2.35 (3H, s); 2.19 (1H, m); 2.06 (1H, m); 1.86 (1H, t, J=5.7); 1.80 (1H,m); 1.64 (2H, m); 1.41 (1H, m); 1.33-1.19 (2H, m); 1.27 (3H, s), 1.21(3H, s); 1.16 (1H, d, J=10.6); 0.82 (3H, d); 0.80 (3H, d); 0.78 (3H, s).

Example C.5 2-S-amino-3-(hexanoylamino)-propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl],hydrochloride salt

2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(hexanoylamino)propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl],of Example B.5, (450 mg, 0.8 mmol, 1 eq.), was dissolved in 1,4-dioxane(15 ml). To this solution, HCl 4N in 1,4-dioxane (2.45 ml, 0.98 mmol, 12eq.) was added and the solution stirred overnight at r.t. The solventwas removed under reduced pressure to give 400 mg of a glassy solid.Yield quantitative.

Analytical data: ¹H NMR (DMSO-d₆).

δ_(H): 8.54 (1H, d, J=5.3 Hz); 8.18 (3H, br); 7.74 (1H, t, J=5.7); 4.29(1H, dd, J=1.8, 8.8); 3.83 (1H, m); 3.40 (2H, m); 3.00 (1H, m); 2.29(1H, m); 2.11 (1H, m); 2.08 (2H, t, J=7.5); 1.93 (1H, t, J=5.5); 1.84(1H, m); 1.75-1.15 (11H, m); 1.32 (3H, s); 1.24 (3H, s); 0.86 (3H, d,J=6.6); 0.84 (3H, d, J=6.6); 0.81 (3H, s).

Example C.6 2-S-amino-3-(4-Fluorosulfonylamino)propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl],hydrochloride salt

2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(4-fluorosulfonylamino)propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl],of Example B.6, (0.7 g, 1.14 mmol, 1 eq.), was dissolved in 1,4-dioxane(20 ml). To this solution, HCl 4N in 1,4-dioxane (3.4 ml, 13.68 mmol, 12eq.) was added and the solution stirred overnight at r.t. The solventwas removed under reduced pressure to give 440 mg of a white solid.Yield 71%. Analytical data:

¹H NMR (DMSO-d₆).

δ_(H): 8.54 (1H, d, J=5.5 Hz); 8.26 (3H, br); 7.89 (3H, m); 7.48 (3H, t,J=8.8); 4.26 (1H, dd, J=1.3, 8.6); 3.84 (1H, m); 3.06 (2H, m); 2.97 (1H,m); 2.25 (1H, m); 2.03 (1H, m); 1.83 (2H, m); 1.64 (2H, m); 1.42 (1H,m); 1.35-1.15 (3H, m); 1.28 (3H, s); 1.22 (3H, s); 1.11 (1H, d, J=10.8);0.85 (6H, m); 0.80 (3H, s).

Example C.7 2-S-amino-3-(3,4-Dimethoxyphenylacetamido)propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl],hydrochloride salt

2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(3,4-dimethoxyphenylacetamido)-propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl],of Example B.7, (0.3 g, 0.47 mmol, 1 eq.), was dissolved in 1,4-dioxane(20 ml). To this solution, HCl 4N in 1,4-dioxane (1.43 ml, 5.71 mmol, 12eq.) was added and the solution stirred overnight at r.t. The solventwas removed under reduced pressure, diethyl ether was added andevaporated to give 230 mg of a white solid. Yield 85%.

Analytical data:

¹H NMR (DMSO-d₆).

δ_(H): 8.57 (1H, br); 8.12 (3H, br); 7.91 (1H, t, J=5.7 Hz); 6.86 (2H,m); 6.76 (1H, dd, J=1.8, 8.2); 4.26 (1H, br d, J=7.3); 3.82 (1H, m);3.72 (3H, s); 3.71 (3H, s); 3.36 (2H, s); 3.34 (2H, m); 2.99 (1H, m);2.26 (1H, m); 2.10 (1H, m); 1.92 (1H, t, J=5.3); 1.83 (1H, m); 1.67 (2H,m); 1.45-1.15 (3H, m); 1.31 (3H, s); 1.23 (3H, s); 0.86 (3H, d, J=6.6);0.84 (3H, d, J=6.6); 0.80 (3H, s).

Example C.8 2-S-amino-3-(3-phenyl-ureido)-propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl],Hydrochloride Salt

2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(3-phenylureido)propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl],of Example B.8, (0.58 g, 0.1 mmol, 1 eq.), was dissolved in 1,4-dioxane(25 ml). To this solution, HCl 4N in 1,4-dioxane (3 ml, 12.1 mmol, 12eq.) was added and the solution stirred overnight at r.t. The solventwas removed under reduced pressure, diethyl ether was added andevaporated to give 0.52 g of desired product. Yield 100%.

Analytical data:

¹H NMR (DMSO-d₆).

δ_(H): 8.82 (1H, s); 8.59 (1H, d, J=5.7 Hz); 8.18 (3H, br); 7.40 (2H, d,J=7.9); 7.22 (2H, t, J=8.1); 6.90 (1H, t, J=7.3); 6.31 (1H, t, J=5.7);4.26 (1H, dd, J=1.5, 8.6); 3.89 (1H, m); 3.48 (1H, m); 3.36 (1H, m);3.01 (1H, m); 2.24 (1H, m); 2.10 (1H, m); 1.92 (1H, t, J=5.3); 1.82 (1H,m); 1.67 (2H, m); 1.50-1.15 (3H, m); 1.31 (3H, s); 1.21 (3H, s); 0.85(3H, d, J=6.6); 0.84 (3H, d, J=6.6); 0.79 (3H, s).

Example C.9 Synthesis of Further Compounds

Following the procedures of Examples C.4-C.8, the following compoundscan be prepared starting from intermediates of Example B.9.

C.9.1 2-S-amino-3-(acetamido)-propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl], HClsalt.

C.9.2 2-S-amino-3-(9-fluorenylmethyloxycarbamoyl)-propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl], HCl salt.

C.9.3 2-S-amino-3-(pentylureido)-propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl],HCl salt.

C.9.4 2-S-amino-3-(methanesolfonamido)-propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl], HCl salt.

C.9.5 2-S-amino-3-[(ethoxycarbonylsuccinyl]-amide)ethyl]-)-propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl], HCl salt.

C.9.6 2-S-amino-3-(benzyloxycarbamoyl)-propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl], HCl salt.

C.9.7 3-[2-(1H-pyrazol)ethyl]-N-[(1S)-1-[[[(1R)-1-[(3aS,aS,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl-]- 3-methylbutyl]amino]carbonyl] HClsalt.

Example D.1 Decanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl]-

To a solution of decanoic acid (0.84 g, 4.83 mmol) in anhydrous DMF (30ml) HATU (1.84 g, 4.83 mmol) and HOAt (0.66 g, 4.83 mmol) were added.After stirring at room temperature for 15 minutes the mixture was cooledat 0° C. and N-methylmorpholine (1.33 ml, 12.1 mmol) was added. Afterfurther 20 minutes(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]pentanamide,N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]-hydrochloridesalt of Example C.1 (2.2 g, 4.03 mmol) was added. The mixture wasallowed to warm to room temperature and stirred for 5 hours, thendiluted with ethyl acetate (150 ml), washed with a 2% solution of citricacid (2×100 ml), 2% solution of NaHCO₃ (2×100 ml), and 2% solution ofNaCl (2×100 ml). The organic phases were dried over sodium sulfate andconcentrated. The residue was purified by column chromatography elutingwith AcOEt/n-Hexane mixtures from 80/20 to 100/0. The resulting solidwas triturated with diethyl ether, collected by filtration and driedunder vacuum giving 1.8 g of product (72% yield).

M.P. 89-94° C.

El. Anal. Calculated: C 59.99% H 9.26% N 13.54% Found C 59.47% H 9.51% N13.42%

¹H NMR (DMSO-d₆): 8.82 (1H, d, J=2.7 Hz); 8.53 (1H, br); 7.99 (1H, d,J=8.05); 7.88 (2H, br); 4.33 (1H, m); 4.08 (1H, dd, J=1.6, 8.6); 3.14(2H, m); 2.56 (1H, m); 2.20 (1H, m); 2.11 (2H, m); 2.01 (1H, m); 1.84(1H, t, J=5.7); 1.79 (1H, m); 1.74-1.58 (3H, m); 1.57-1.39 (5H, m); 1.32(1H, d, J=9.9); 1.24 (19H, m); 0.85 (9H, m); 0.80 (3H, s).

Starting with the(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-pentanamide,N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]hydrochloridesalt of Example C.1 and the appropriate carboxylic acids, furthercompounds prepared fundamentally in accordance with the aboveexperimental procedures are reported in Table D-1.

Ex # Structure Chemical Name and Analytical Data D.1.1

Chemical Name: Naphthalen-2-carboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: 1H-NMR(DMSO-d6): 8.97 (1H, d, J = 2.8 Hz); 8.71 (1H, d,J = 8.0 Hz); 8.54 (1H, br); 8.50 (1H, s); 8.1-7.9 (4H, m); 7.85 (2H,br); 7.6 (2H, m); 4.63 (1H, m); 4.09 (1H, m); 3.20 (2H, m); 2.61 (1H,m); 2.20 (1H, m); 2.01 (1H, m); 1.9-1.2 (11H, m); 1.23 (3H, s); 1.21(3H, s); 0.85 (6H, d, J = 6.6): 0.79 (3H, s). D.1.2

Chemical Name: 2-Pyrazinecarboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [imino(nitroamino)methyl]amino]butyl]-Analytical Data: 1H-NMR(DMSO-d6): 9.18 (1H, d, J = 1.3 Hz); 8.89 (1H, d,J = 2.4); 8.8-8.65 (3H, m): 8.5 (2H, br); 4.59 (1H, m); 4.15 (1H, dd, J= 1.8, 8.6); 3.14 (2H, m); 2.72 (1H, m); 2.20 (1H, m); 2.02 (1H, m);1.9-1.2 (11H, m); 1.23 (3H, s); 1.21 (3H, s); 0.83 (6H, 2 d, J = 6.6);0.79 (3H, s). D.1.3

Chemical Name: 3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-propanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: 1H-NMR (DMSO-d6): 8.79 (1H, br); 8.51 (1H, br); 8.44(1H, d, J = 7.8 Hz); 8.2-7.6 (2H, br); 7.85 (4H, m); 4.30 (1H, m); 4.081H, dd, J = 1.8, 8.6); 3.78 (2H, t, J = 6.3); 3.11 (2H, m); 2.59 (3H,m); 2.20 (1H, m); 2.01 (1H, m); 1.9-1.2 (11H, m); 1.23 (3H, s); 1.22(3H, s); 0.84 (6H, d, J = 6.6); 0.80 (3H, s). D.1.4

Chemical Name: 4-Butylbenzamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: 1H-NMR(DMSO-d6): 8.93 (1H, d, J = 2.9 Hz); 8.51 (1H,br); 8.24 (1H, d, J = 7.8); 8.2-7.6 (2H, br); 7.86 (2H, d, J = 8.2);7.29 (2H, d, J = 8.2); 4.56 (1H, m); 4.07 1H, dd, J = 1.8, 8.6); 3.16(2H, m); 2.63 (2H, t, J = 7.7); 2.57 (1H, dt, J = 2.5, 7.1); 2.20 (1H,m); 2.01 (1H, m); 1.9-1.2 (15H, m); 1.23 (3H, s); 1.22 (3H, s); 0.90(3H, d, J = 7.3); 0.84 (6H, d, J = 6.6); 0.80 (3H, s). D.1.5

Chemical Name: 3-[(1,1- dimethylethoxy)carbonylamino]benzamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]-Analytical Data: 1H-NMR (DMSO-d6): 9.48 (1H, s); 8.88 (1H, d, J = 2.8Hz); 8.51 (1H, br); 8.42 (1H, d, J = 8.0); 7.6-8.4 (2H, br): 7.97 (1H,s); 7.55 (1H, dd, J = 7.8, 1.1); 7.47 (1H, d, J = 7.8); 7.34 (1H, t, J =7.8); 4.55 (1H, m); 4.09 (1H, dd, J = 1.8, 8.6); 3.17 (2H, m); 2.60 (1H,dt, J = 2.9, 8.4); 2.20 (1H, m); 2.02 (1H, m); 1.9-1.2 (11H, m); 1.48(9H, s); 1.23 (3H, s); 1.21 (3H, s); 0.85 (6H, d, J = 6.6); 0.80 (3H,s). D.1.6

Chemical Name: 2-(2-methoxyethoxy)acetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl Analytical Data: 1H-NMR (DMSO-d6):8.74 (1H, d, J = 2.8 Hz); 8.51 (1H, br); 8.2-7.4 (2H, br); 7.69 (1H, d,J = 8.6); 4.39 (1H, m); 4.12 (1H, dd, J = 1.8, 8.6); 3.91 (2H, s); 3.57(2H, m); 3.46 (2H, t, J = 4.6); 3.26 (3H, s); 3.13 (2H, m); 2.63 (1H,m); 2.21 (1H, m); 2.03 (1H, m); 1.9-1.2 (11H, m); 1.24 (3H, s); 1.21(3H, s); 0.85 (3H, d, J = 6.6); 0.83 (3H, d, J = 6.6); 0.80 (3H, s).D.1.7

Chemical Name: 2-[2-(2-methoxyethoxy)ethoxy]acetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butylAnalytical Data: 1H-NMR (DMSO-d6): 8.74 (1H, d, J = 2.8 Hz); 8.52 (1H,br); 8.2-7.6 (2H, br); 7.69 (1H, d, J = 8.6); 4.40 (1H, m); 4.11 (1H,dd, J = 1.8, 8.6); 3.91 (2H, s); 3.6-3.4 (8H, m); 3.23 (3H, s); 3.13(2H, m); 2.63 (1H, m); 2.20 (1H, m); 2.02 (1H, m); 1.9-1.2 (11H, m);1.24 (3H, s); 1.21 (3H, s); 0.84 (3H, d, J = 6.6); 0.83 (3H, d, J =6.6); 0.79 (3H, s). D.1.8

Chemical Name: (E)-3-(Ethoxycarbonyl)acrylamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl] Analytical Data: 1H-NMR(DMSO-d6): 8.78 (1H, d, J = 8.6 Hz); 8.77 (1H, s); 8.55 (1H, br);8.3-7.6 (2H, br); 7.12 (1H, d, J = 15.5); 6.58 (1H, d, J = 15.5); 4.45(1H, m); 4.19 (2H, q, J = 7.1); 4.12 (1H, dd, J = 1.8, 8.6); 3.15 (2H,m); 2.63 (1H, dt, J = 3.3, 8.6); 2.21 (1H, m); 2.04 (1H, m); 1.9-1.2(11H, m); 1.25 (3H, s); 1.24 (3H, t, J = 6.9); 1.23 (3H, s); 0.85 (3H,d, J = 6.6); 0.83 (3H, d, J = 6.6); 0.80 (3H, s). D.1.9

Chemical Name: 2-Piperidin-1-yl-acetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: 1H-NMR (DMSO-d6): 8.79 (1H, d, J = 1.8 Hz); 8.53 (1H,br); 8.3-7.5 (2H, br); 7.79 (1H, br); 4.37 (1H, m); 4.12 (1H, dd, J =1.8, 8.6); 3.13 (2H, m); 2.87 (2H, br); 2.62 (1H, m); 2.36 (4H, m); 2.20(1H, m); 2.03 (1H, m); 1.9-1.2 (17H, m); 1.24 (3H, s); 1.21 (3H, s);0.83 (6H, d, J = 6.6); 0.79 (3H, s). D.1.10

Chemical Name: 4-(1-Methyl-piperidin-4-yl)-butanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: 1H-NMR (DMSO-d6): 8.82 (1H, d, J = 2.7 Hz); 8.51 (1H,br); 8.01 (1H, d, J = 8.0 Hz); 8.3-7.5 (2H, br); 6.94 (1H, t, J = 5.8):4.33 (1H, m); 4.07 (1H, dd, J = 1.8, 8.6); 3.13 (2H, m); 2.78 (2H, br);2.68 (3H, br s); 2.55 (1H, m); 2.19 (1H, m); 2.10 (2H, t, J = 7.5); 2.00(1H, m); 1.85-1.1 (22H, m); 1.23 (3H, s); 1.21 (3H, s); 0.83 (6H, 2 d, J= 6.6); 0.79 (3H, s). D.1.11

Chemical Name: 2-Acetylamino-acetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: 1H-NMR (DMSO-d6): 8.67 (1H, d, J = 2.7 Hz); 8.51 (1H,br); 8.14 (1H, t, J = 5.7); 8.08 (1H, d, J = 8.0 Hz); 8.3-7.5 (2H, br);4.34 (1H, m); 4.09 (1H, dd, J = 1.8, 8.6); 3.68 (2H, m); 3.13 (2H, m);2.56 (1H, m); 2.20 (1H, m); 2.01 (1H, m); 1.84 (3H, s); 1.85-1.2 (11H,m); 1.24 (3H, s); 1.21 (3H, s); 0.83 (6H, d, J = 6.6); 0.79 (3H, s).

Following the above described procedure for Example D.1 and using asstarting material the(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]pentanamide,N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]-hydrochloridesalt of Example C.1 and the appropriate carboxylic acids, the compoundsreported in Table D-1A are prepared.

TABLE D-1A Ex # Structure Chemical Name and Analytical Data D.1.12

Chemical Name: 6-Benzenesulfonylaminohexanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl] Analytical Data: 1H-NMR(DMSO-d6): 8.83 (1H, d, J = 2.8 Hz); 8.51 (1H, br); 7.97 (1H, d, J = 7.8Hz); 8.2-7.6 (2H, br); 7.77 (2H, m); 7.65-7.5 (4H, m); 4.31 (1H, m);4.05 (1H, dd, J = 1.8, 8.6); 3.12 (2H, m); 2.69 (2H, q, J = 7.0); 2.54(1H, m); 2.20 (1H, m); 2.05 (2H, t, J = 7.5); 2.01 (1H, m); 1.85-1.1(21H, m); 1.22 (3H, s); 1.21 (3H, s); 0.82 (6H, d, J = 6.6); 0.79 (3H,s). D.1.13

Chemical Name: 8-(Ethanesulfonylamino)octanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7 aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl Analytical Data: 1H-NMR (DMSO-d6):8.81 (1H, br s); 8.51 (1H, br); 7.98 (1H, d, J = 7.8 Hz); 8.3-7.5 (2H,br); 6.93 (1H, t, J = 5.7): 4.32 (1H, m); 4.06 (1H, dd, J = 1.8, 8.6);3.13 (2H, m); 2.95 (2H, q, J = 7.3); 2.87 (2H, q, J = 6.7); 2.55 (1H,m); 2.19 (1H, m); 2.10 (2H, t, J = 7.0); 2.00 (1H, m); 1.85-1.1 (17H,m); 1.23 (3H, s); 1.21 (3H, s); 1.16 (3H, t, J = 7.3); 0.83 (6H, d, J =6.6); 0.79 (3H, s). D.1.14

Chemical Name: 6-(Ethanesulfonylamino)hexanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl] Analytical Data: 1H-NMR(DMSO-d6): 8.83 (1H, d, J = 2.7 Hz); 8.51 (1H, br); 8.00 (1H, d, J = 8.0Hz); 8.3-7.5 (2H, br); 6.94 (1H, t, J = 5.8): 4.32 (1H, m); 4.06 (1H,dd, J = 1.8, 8.6); 3.13 (2H, m); 2.95 (2H, q, J = 7.3); 2.87 (2H, q, J =6.7); 2.55 (1H, m); 2.19 (1H, m); 2.10 (2H, t, J = 7.5); 2.00 (1H, m);1.85- 1.1 (17H, m); 1.24 (3H, s); 1.21 (3H, s); 1.16 (3H, t, J = 7.5);0.83 (6H, d, J = 6.6); 0.79 (3H, s).

Example D.2 10-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-decanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl]-;

To a solution of 10-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-decanoic acid(353 mg, 1.11 mmol), prepared according to Example G.1, in anhydrousdichloromethane (10 ml), N-methylmorpholine was added (122 μl, 1.11mmol). The mixture was cooled to −15° C., then isobutyl chloroformate(144 μl, 1.11 mmol) was slowly added. After 15 minutes(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]pentanamide,N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]-hydrochloridesalt of Example C.1 (508 mg, 1.01 mmol) and further N-methylmorpholine(122 μl, 1.11 mmol) were added. The reaction mixture was stirred at −15to 10° C. for 4 h, then concentrated to small volume and partitionedbetween ethyl acetate (20 ml) and water (10 ml). The aqueous phase wasfurther extracted with ethyl acetate (10 ml). The combined organicphases were dried over sodium sulfate and concentrated. The residue wastaken up with ethyl acetate (3 ml) and the solution was dropwise addedto hexane (120 ml) while stirring at room temperature. The solid wascollected by decantation and dried under vacuum (730 mg, 94%).

¹H NMR (DMSO-d₆): 8.81 (1H, d, J=2.7 Hz); 8.52 (1H, br); 7.98 (1H, d,J=8.05); 7.88 (2H, br); 7.85 (4H, m); 4.34 (1H, m); 4.06 (1H, dd,J=7.1); 3.56 (2H, t, J=7.14); 3.14 (2H, m); 2.55 (1H, m); 2.19 (1H, m);2.10 (2H, t, J=7.14); 2.0 (1H, m); 1.82 (1H, t, J=5.7); 1.78 (1H, m);1.73-1.35 (10H, m); 1.31 (1H, d, J=9.9); 1.24 (19H, m); 0.84 (9H, m);0.79 (3H, s).

Further compounds prepared fundamentally in accordance with the aboveexperimental procedures are reported in Table D-2.

TABLE D-2 Ex # Structure Chemical Name and Analytical Data D.2.1

Chemical Name: 4-(methoxycarbonyl)butanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl] Analytical Data: 1H-NMR(DMSO-d6): 8.79 (1H, d, J = 2.7 Hz); 8.51 (1H, br); 8.04 (1H, d, J = 7.9Hz); 8.3-7.5 (2H, br); 4.31 (1H, m); 4.07 (1H, dd, J = 1.8, 8.6); 3.57(3H, s); 3.13 (2H, m); 2.55 (1H, m); 2.28 (2H, t, J = 7.7); 2.20 (1H,m); 2.28 (2H, t, J = 7.5); 2.01 (1H, m); 1.85-1.2 (13H, m); 1.23 (3H,s); 1.21 (3H, s); 0.83 (6H, d, J = 6.6); 0.79 (3H, s). D.2.2

Chemical Name: 4-(1-Butyl-piperidin-4-yl)-butanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl] Analytical Data: 1H-NMR(DMSO-d6): 8.78 (1H, d, J = 2.7 Hz); 8.51 (1H, br); 7.97 (1H, d, J = 8.0Hz); 8.3-7.5 (2H, br); 4.32 (1H, m); 4.07 (1H, dd, J = 1.8, 8.6); 3.13(2H, m); 2.78 (2H, br d, J = 11.2); 2.55 (1H, m); 2.19 (3H, m); 2.09(2H, t, J = 7.5); 2.00 (1H, m); 1.85-1.0 (26H, m); 1.23 (3H, s); 1.21(3H, s); 0.85 (3H, t, J = 7.9); 0.83 (6H, 2 d, J = 6.6); 0.79 (3H, s).D.2.3

Chemical Name: 2-Butoxyacetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl] Analytical Data: 1H-NMR(DMSO-d6): 8.74 (1H, d, J = 2.8 Hz); 8.51 (1H, br); 8.3-7.5 (2H, br);7.61 (1H, d, J = 8.0); 4.39 (1H, m); 4.12 (1H, br d, J = 8.2); 3.85 (2H,s); 3.42 (2H, t, J = 6.4); 3.13 (2H, m); 2.64 (1H, m); 2.20 (1H, m);2.03 (1H, m); 1.95-1.2 (15H, m); 1.24 (3H, s); 1.21 (3H, s); 0.87 (3H,t, J = 7.3); 0.83 (6H, d, J = 6.6); 0.79 (3H, s).

Further compounds prepared according to the above reported procedure inExample D.2 are reported in Table D-2A The compound of Example D.2.6,was prepared starting from 2-aminoacetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]-amino]carbonyl]-4-[[imino(nitroamino)methyl]-amino]-butyl],hydrochloride salt of Example D.14. The compounds of example D.2.7 andD.2.8 were prepared from 2-aminoacetamide,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-1-methylbutyl];hydrochloride salt of Example C.3. The compounds of Examples 2.9 and2.10 were prepared from (2S)-2-amino-5-ureidopentanamide,N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl];hydrochloride salt of Example C.3

TABLE D-2A Ex # Structure Chemical Name and Analytical Data D.2.4

Chemical Name: 12-[(1,1- dimethylethoxy)carbonylamino] dodecanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]-Analytical Data: 1H NMR (DMSO-d6) 8.81 (1H, d, J = 2.4); 8.52 (1H, br);7.98 (1H, d, J = 8.05); 7.85 (2H, v. br); 6.73 (1H, t, J = 5.3); 4.33(1H, m); 4.07 (1H, d, J = 8.4); 3.14 (2H, m); 2.88 (2H, q, J = 6.6);2.56 (1H, m); 2.19 (1H, m); 2.10 (2H, t, J = 7.1); 2.01 (1H, m); 1.83(1H, t, J = 5.7); 1.78 (1H, m); 1.73- 1.41 (8H, m); 1.36 (9H, s);1.33-1.15 (25H, m); 0.84 (6H, d, J = 6.5); 0.80 (3H, s). D.2.5

Chemical Name: 4-(methoxycarbonyl)heptanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl] Analytical Data: 1H-NMR(DMSO-d6): 8.80 (1H, br s); 8.51 (1H, br); 7.98 (1H, d, J = 8.0 Hz);8.3-7.5 (2H, br); 4.32 (1H, m); 4.06 (1H, br d, J = 8.4); 3.12 (2H, m);2.55 (1H, m); 2.26 (2H, t, J = 7.3); 2.18 (1H, m); 2.09 (2H, t, J =7.1); 2.01 (1H, m); 1.85-1.2 (19H, m); 1.23 (3H, s); 1.21 (3H, s); 0.83(6H, d, J = 6.6); 0.79 (3H, s). D.2.6

Chemical Name: 2-[2-(2-methoxyethoxy)acetylamino]acetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butylAnalytical Data: 1H-NMR (DMSO-d6): 8.71-8.68 (1H, m); 8.53 (1H, m); 8.15(1H, d, J = 8.1); 8.10-7.60 (3H, m); 4.40-4.33 (1H, m); 4.13-4.08 (1H,m); 3.92 (2H, s); 3.82-3.78 (2H, m); 3.64-3.58 (2H, m); 3.52- 3.46 (2H,m); 3.27 (3H, s); 2.62-2.56 (1H, m); 2.26-2.16 (1H, m); 2.08-2.00 (1H,m); 1.85 (1H, t, J = 5.5); 1.82-1.76 (1H, m); 1.72-1.60 (3H, m);1.59-1.40 (4H, m); 1.32-1.26 (4H, m); 1.25 (3H, s); 1.22 (3H, s);0.86-0.83 (6H, m); 0.81 (3H, s). D.2.7

Chemical Name: Decanamide,N-[1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]methyl] Analytical Data: 1H-NMR (DMSO-d6):8.85 (1H, s); 8.11 (1H, t, J = 5.9); 4.07-4.03 (1H, m); 3.83-3.78 (2H,d, J = 6.4); 2.24-2.16 (1H, m); 2.11 (2H, t, J = 7.40); 2.05-1.95 (1H,m); 1.84 (1h, t, J = 5.6); 1.81-1.75 (1H, m); 1.74-1.60 (2H, m);1.54-1.45 (2H, m); 1.35-1.30 (1H, d, J = 10.1); 1.28-1.20 (21H, m);0.90-0.84 (9H, m); 0.81 (3H, s). D.2.8

Chemical Name: 2-[2-(2-methoxyethoxy) ethoxy]acetamide,N-[1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]methyl] Analytical Data: 1H-NMR(DMSO-d6): 8.81 (1H, m); 7.97 (1H, t, J = 6.0); 4.09-4.04 (1H, m); 3.93(2H, s); 3.85 (2H, d, J = 6.0); 3.64-3.57 (2H, m); 3.57-3.50 (4H, m);3.45-3.40 (2H, m); 3.23 (3H, s); 2.58-2.52 (1H, m); 2.24-2.15 (1H, m);2.05-1.97 (1H, m); 1.83 (1H, t, J = 5.6); 1.80-1.76 (1H, m); 1.72-1.58(2H, m); 1.31 (1H, d, J = 10.1); 1.28-1.25 (2H, m); 1.23 (3H, s); 1.21(3H, s); 0.86-0.82 (6H, m); 0.80 (3H, s). D.2.9

Chemical Name: Decanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-5-ureidopentyl]- D.2.10

Chemical Name: 4-Butylbenzamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-5-ureidopentyl]-

Example D.3 11-Cyanoundecanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl]-

PS-Carbodiimide (N-cyclohexylcarbodiimide-N′-propyloxymethylpolystyrene, 769 mg, 1 mmol, loading 1.31 mmol/g) and HOAt(1-Hydroxy-7-azabenzotriazole, 115 mg, 0.85 mmol) were added to asolution of 11-cyanoundecanoic acid (115 mg, 0.54 mmol) indichloromethane (DCM) (9 mL). After stirring for 10 minutes(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]pentanamide,N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]-,hydrochloride salt of Example C.1 (251 mg, 0.50 mmol) and DIPEA (0.128ml, 0.75 mmol) were added. The suspension was shaken overnight at roomtemperature and then the PS-Carbodiimide was filtered off and washedseveral times with DCM (4×6 mL).

The organic phase was passed through a VARIAN CHEM ELUT cartridge forliquid-liquid extraction pre-conditioned with saturated aqueous NaHCO₃and finally washed with DCM (15 mL). The solvent was evaporated and thecrude reaction was purified with normal-phase ISOLUTE SPE-SI column (DCM9, MeOH 1) to afford 200 mg of the desired compound (yield 61%).

NMR (CDCl₃): 7.53 (s, br, 2H); 7.36 (d, br, J=4.7 Hz, 1H); 6.88 (d,J=8.2 Hz, 1H); 4.46 (m, 1H); 4.15 (dd, J=8.5, 1.9 Hz, 1H); 3.19 (m, 2H);2.93 (m, 1H); 2.23 (t, J=7.2 Hz, 2H); 2.21 (m, 1H); 2.09 (t, J=7.5, 2H);2.04 (m, 1H); 1.88 (t, J=5.4 Hz, 1H); 1.77 (m, 1H); 1.69 (m, 1H);1.64-1.43 (m, 9H); 1.40-1.26 (m, 4H); 1.26 (s, 3H); 1.24-1.12 (m, 16H);0.80 (d, J=6.6, 3H); 0.79 (d, J=6.6, 3H); 0.73 (s, 3H).

LC-MS 659.7, MH+. ESI POS; AQA; spray 4 kV/skimmer: 20V/probe 250 C.

Further compounds prepared fundamentally in accordance with the aboveexperimental procedures are reported in Table D-3.

TABLE D-3 Ex # Structure Chemical Name and Analytical Data D.3.1

Chemical Name: Decanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+ 621.5D.3.2

Chemical Name: Naphthalen-1-carboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 621.4 D.3.3

Chemical Name: 2-Phenylacetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+ 585.3D.3.4

Chemical Name: 1-Phenylcyclopentanecarboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 639.4 D.3.5

Chemical Name: (2R)-2-Phenylbutanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 613.4 D.3.6

Chemical Name: (2S)-2-Phenylbutanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 613.4 D.3.7

Chemical Name: Dodecanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+ 649.5D.3.8

Chemical Name: Octanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+ 593.4D.3.9

Chemical Name: Acetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+ 509.3D.3.10

Chemical Name: 4-(1,1- Dimethylethyl)cyclohexanecarboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 633.5 D.3.11

Chemical Name: trans-4-Pentylcyclohexanecarboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 647.5 D.3.12

Chemical Name: 4-Phenylbutanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+ 613.4D.3.13

Chemical Name: 2-(3-Methoxyphenyl)acetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 615.3 D.3.14

Chemical Name: 4-(1,1-Dimethylethyl)benzamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 627.5 D.3.15

Chemical Name: Nonanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+ 607.4D.3.16

Chemical Name: (RS)-2-Cyclopentylhexanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 633.5 D.3.17

Chemical Name: Thiophene-2-carboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 577.2 D.3.18

Chemical Name: 2,3-Difluorobenzamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 607.3 D.3.19

Chemical Name: 2-(2-Iodophenyl)acetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 711.3 D.3.20

Chemical Name: Cyclohexanecarboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 577.3 D.3.21

Chemical Name: 2-(4-Bromophenyl)acetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 663.2 D.3.22

Chemical Name: Benzamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+ 571.3D.3.23

Chemical Name: 2-Methylbenzamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+ 585.3D.3.24

Chemical Name: 4-Bromobenzamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+ 649.3D.3.25

Chemical Name: (2S)-2-Phenylpropanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 599.3 D.3.26

Chemical Name: (E)-2-Methyl-3-phenyl-acrylamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 611.4 D.3.27

Chemical Name: 2-[(Naphthalen-2-yl)oxy]acetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 651.4 D.3.28

Chemical Name: 2,2-Dimethylbutanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 565.4 D.3.29

Chemical Name: 2-(2-Chlorophenyl)acetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 619.3 D.3.30

Chemical Name: 5-Methylthiophene-2-carboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 591.3 D.3.31

Chemical Name: cis-3-(2-Methoxyphenyl)acrylamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 627.4 D.3.32

Chemical Name: (2-Methylphenoxy)acetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 615.4 D.3.33

Chemical Name: 2-(2,5-Dimethylphenyl)acetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 613.4 D.3.34

Chemical Name: trans-3-(2-Bromophenyl)acrylamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 675.3 D.3.35

Chemical Name: 4-Isopropylbenzamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+ 613.4D.3.36

Chemical Name: 4-(4-methylphenyl)butanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 627.4 D.3.37

Chemical Name: 2-(2-Naphthylsulfanyl)acetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 667.3 D.3.38

Chemical Name: 5-Methylhexanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+ 579.4D.3.39

Chemical Name: 3-Thiophen-2-yl-propanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 605.4 D.3.40

Chemical Name: 2,4-Dimethylthiazole-5-carboxamide,N-[(1S)-1-[[[(1R)-1-[(3a,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 606.4 D.3.41

Chemical Name: Furan-3-carboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+ 561.3D.3.42

Chemical Name: (2R)-2-Phenylpropanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [immo(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 599.4 D.3.43

Chemical Name: 2-Cycloheptylacetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5,trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 605.4 D.3.44

Chemical Name: 1-Methylcyclopropanecarboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 549.3 D.3.45

Chemical Name: 1-Methyl-cyclohexanecarboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 591.3 D.3.46

Chemical Name: 2-[(1S,2R,5S)-2-isopropyl-5-methylcyclohexyl]oxyacetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 663.3 D.3.47

Chemical Name: (E)-2-Butenamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]ammo]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+ 535.6D.3.48

Chemical Name: 3-Methylbutanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[[imino(mtroamino)methyl]amino]butyl] Analytical Data: MS: MH+ 551.3D.3.49

Chemical Name: 3-Phenylpropanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+ 599.3D.3.50

Chemical Name: 4-(4-Methoxyphenyl)-butanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 643.4 D.3.51

Chemical Name: Thiophene-3-carboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 577.2 D.3.52

Chemical Name: 2-Thiophen-3-yl-acetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylhutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 591.4 D.3.53

Chemical Name: (E)-Penta-2,4-dienoic acid amide,N-[(1S)-l-[[[(1R)-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 547.3 D.3.54

Chemical Name: 2-(4-Isopropylphenoxy)acetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 643.4 D.3.55

Chemical Name: 2-(4-Ethylphenoxy)acetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 629.4 D.3.56

Chemical Name: (E)-2-Methylhex-2-enoic acid amide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroammo)methyl]amino]butyl]Analytical Data: MS: MH+ 577.2 D.3.57

Chemical Name: 3-(3-Methylphenyl)acrylamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 611.4 D.3.58

Chemical Name: 2-Adamantan-1-ylacetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 643.3 D.3.59

Chemical Name: (RS)-2-Cyclopent-2-enylacetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [immo(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 575.3 D.3.60

Chemical Name: 4-Diethylaminobenzamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 642.4 D.3.61

Chemical Name: (RS)-2-Methylbutanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 551.3 D.3.62

Chemical Name: 3-(4-Methylphenyl)acrylamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 611.4 D.3.63

Chemical Name: Hexa-2,4-dienoic acid amide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 561.5 D.3.64

Chemical Name: 4-Pyrrol-1-yl-benzamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 636.3 D.3.65

Chemical Name: (E)-3-Thiophen-3-yl-acrylamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 603.3 D.3.66

Chemical Name: Hept-2-enamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+ 577.3D.3.67

Chemical Name: 2-(3,4-Dimethylphenoxy)acetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 629.3 D.3.68

Chemical Name: Dec-9-enamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+ 619.3D.3.69

Chemical Name: (E)-Undec-2-enoic acid amide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 633.4 D.3.70

Chemical Name: (E)-Dec-3-enoic acid amide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 619.4 D.3.71

Chemical Name: 2,2-Dimethyl-3-(2-methylpropenyl)-cyclopropanecarboxamide,N-[(1S)-1- [[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 616.9 D.3.72

Chemical Name: 2-Methylcyclohexanecarboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 591.4 D.3.73

Chemical Name: 5-Cyclohexylpentanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 633.5 D.3.74

Chemical Name: 3-Methoxycyclohexanecarboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 607.3 D.3.75

Chemical Name: (3R)-3,7-Dimethyl-oct-6-enoic acidamide,N-[(1S)-1-[[[(1R)-1- [(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 619.4 D.3.76

Chemical Name: 3-[(4- methylbenzyl)sulfanyl]propanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 659.3 D.3.77

Chemical Name: (3S)-3,7-Dimethyl-oct-6-enoic acidamide,N-[(1S)-1-[[[(1R)-1- [(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 619.4 D.3.78

Chemical Name: (RS)-4-Ethyloctanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 621.4 D.3.79

Chemical Name: 5-Fluoro-2-methoxybenzamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 619.2 D.3.80

Chemical Name: 2-(4-Bromophenoxy)-acetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 679.6 D.3.81

Chemical Name: 2-(1-Methyl-1H-indol-3-yl)acetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 638.3 D.3.82

Chemical Name: Hexahydro-2,5-methanopentalene-3a(1H)-carboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+ 615.2D.3.83

Chemical Name: Bicyclo[2.2.1]heptane-2-carboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 589.2 D.3.84

Chemical Name: (RS)-2-(4-Chlorophenyl)propionamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 633.6 D.3.85

Chemical Name: (2S)-2-methylbutanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 551.8 D.3.86

Chemical Name: (4RS)-1-[(1,1-dimethylethoxy)carbonyl]-piperidine-4-carboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 678.4 D.3.87

Chemical Name: (RS)-4-Methyloctanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 607.3 D.3.88

Chemical Name: 2-Fluoro-5-methylbenzamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 603.2 D.3.89

Chemical Name: 2-(Bicyclo[2.2.1]hept-2-yl)acetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 603.8 D.3.90

Chemical Name: Cyclopropanecarboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 535.3 D.3.91

Chemical Name: 4-Ethoxybenzamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+ 615.2D.3.92

Chemical Name: (E)-3-(4-Bromophenyl)acrylamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 675.1 D.3.93

Chemical Name: (2S)-2-(6-Methoxynaphthalen-2-yl)-propanamide,N-[(1S)-1-[[[(1R)-1- [(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 679.3 D.3.94

Chemical Name: 3-Fluoro-4-methoxybenzamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 619.5 D.3.95

Chemical Name: 4-Fluoro-3-methylbenzamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 603.2 D.3.96

Chemical Name: Non-2-enoic acid amide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 605.3 D.3.97

Chemical Name: (E)-3-(Naphthalen-2-yl)acrylamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 647.3 D.3.98

Chemical Name: Quinoline-2-carboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 622.3 D.3.99

Chemical Name: 1-(4-Methoxyphenyl)- cyclopropanecarboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 641.4 D.3.101

Chemical Name: 3-Butenamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+ 535.0D.3.102

Chemical Name: Tetradecanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+ 677.3D.3.103

Chemical Name: 3-(1H-Indol-3-yl)-propanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 638.2 D.3.104

Chemical Name: 4-Phenoxybutanamide,N-[(1S)-1-[[[(1R)-[[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+ 628.9D.3.105

Chemical Name: 5-Oxo-5-phenyl-pentanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-l,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 641.1 D.3.106

Chemical Name: (2RS)-1-((1,1-dimethylethoxy)carbonyl)-piperidine-2-carboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 678.2 D.3.107

Chemical Name: Pyridine-2-carboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 572.1 D.3.108

Chemical Name: Pyridine-3-carboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 572.1 D.3.109

Chemical Name: Pyridine-4-carboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 572.5 D.3.110

Chemical Name: (2S)-1-((1,1-dimethylethoxy)carbonyl)-piperidine-2-carboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 678.1 D.3.111

Chemical Name: (2R)-1-((1,1-dimethylethoxy)carbonyl)-piperidine-2-carboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 678.2 D.3.112

Chemical Name: 3,3-Dimethyl-butanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 565.0 D.3.113

Chemical Name: 4-[(Phenylamino)carbonyl]butanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 656.2 D.3.114

Chemical Name: 2,2-Dimethylpentanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 579.2 D.3.115

Chemical Name: 5-Thiophen-2-yl-pentanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 633.2 D.3.116

Chemical Name: (3RS)-1-((1,1-dimethylethoxy)carbonyl)-piperidine-3-carboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 678.0 D.3.117

Chemical Name: 8-Phenyl-octanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+ 669.1D.3.118

Chemical Name: 3-[[(1,1- dimethylethoxy)carbonyl]amino]propanamide,N-[(1S)-1-[[[(1R)-1- [(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 638.2 D.3.119

Chemical Name: Tridecanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+ 663.3D.3.120

Chemical Name: Succinamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+ 566.1D.3.121

Chemical Name: Pentanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+ 551.2D.3.122

Chemical Name: [[[(9H-fluoren-9- yl)methoxy]carbonyl]amino]butanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 775.3 D.3.123

Chemical Name: 2-(Dimethylamino)acetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 552.5 D.3.124

Chemical Name: 5-(4-Fluorophenyl)-pentanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 645.2 D.3.125

Chemical Name: 8-Oxo-8-phenyloctanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-l,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 683.1 D.3.126

Chemical Name: 4-(Thiophen-2-yl)butanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 619.0 D.3.127

Chemical Name: 5-Oxo-5-(thiophen-2-yl)pentanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: MH+ 647.1 D.3.128

Chemical Name: 2-(3-Chlorophenyl)acetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: [MH]+ 619.1 D.3.129

Chemical Name: Undecanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+ 635.2D.3.130

Chemical Name: 4-Heptylbenzamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+ 669.6D.3.131

Chemical Name: 6-Phenylhexanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+ 641.5D.3.132

Chemical Name: 5-Phenylpentanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+ 627.5D.3.133

Chemical Name: 10-Hydroxydecanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: [MH]+ 637.7 D.3.134

Chemical Name: 5-Oxo-5-(4-phenylpiperazin-1-yl)pentanamide,N-[(1S)-1-[[[(1R)-1- [(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: [MH]+ 725.4 D.3.135

Chemical Name: 2-(1H-Tetrazol-5-yl)acetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: [MH]+ 577.0 D.3.136

Chemical Name: 2-(Tetrazol-1-yl)acetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: [MH]+ 576.9 D.3.137

Chemical Name: 2-(Pyrimidin-2-ylsulfanyl)acetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: [MH]+ 618.9 D.3.138

Chemical Name: 3-Methylsulfanylpropanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: [MH]+ 569.4 D.3.139

Chemical Name: 3-(Naphthalen-2-ylsulfanyl)-propanamide,N-[(1S)-1-[[[(1R)-1- [(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: [MH]+ 681.5 D.3.140

Chemical Name: 2-[(Phenylmethyl)sulfanyl]acetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: [MH]+ 631.5 D.3.141

Chemical Name: 6-Oxoheptanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+ 593.5D.3.142

Chemical Name: 4-(4-Methanesulfonylphenyl)-4-oxobutanamide,N-[(1S)-1-[[[(1R)-1- [(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: [MH]+ 705.0 D.3.143

Chemical Name: (2S)-1-Acetylpyrrolidine-2-carboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: [MH]+ 605.9 D.3.144

Chemical Name: 3-Hydroxy-2,2-dimethylpropanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: [MH]+ 566.9 D.3.145

Chemical Name: 2-Ethylsulfanylacetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: [MH]+ 569.8 D.3.146

Chemical Name: 3-Ureidopropanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+ 581.5D.3.147

Chemical Name: 3-Methoxypropanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: [MH]+ 552.9 D.3.148

Chemical Name: 2-Methylsulfanylacetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: [MH]+ 555.6 D.3.149

Chemical Name: 3H-Imidazole-4-carboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: [MH]+ 561.0 D.3.150

Chemical Name: 7-Oxo-octanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+ 607.1D.3.151

Chemical Name: (E)-3-(Imidazol-4-yl)acrylamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: [MH]+ 587.4 D.3.152

Chemical Name: (RS)-Tetrahydrofuran-3-carboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: [MH]+ 565.3 D.3.153

Chemical Name: (E)-3-(2-Methoxyphenyl)acrylamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: [MH]+ 627.7 D.3.154

Chemical Name: 2-Ethoxyacetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+ 553.0D.3.155

Chemical Name: 3-Furan-2-yl-propanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: [MH]+ 589.5 D.3.156

Chemical Name: 3-(Benzenesulfonyl)propanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [immo(nitroamino)methyl]amino]butyl]Analytical Data: MS: [MH]+ 663.0 D.3.157

Chemical Name: 4-Sulfamoylbutanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: [MH]+ 615.8 D.3.158

Chemical Name: (4S)-2-Oxo-1,3-thiazolidine-4-carboxamide,N-[(1S)-1-[[[(1R)-1- [(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[immo(nitroamino)methyl]amino]butyl]Analytical Data: MS: [MH]+ 595.8 D.3.159

Chemical Name: (2R)-1-Acetylpyrrolidine-2-carboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: [MH]+ 605.9 D.3.160

Chemical Name: 3-[(Acetylamino)methylsulfanyl]-propanamide,N-[(1S)-1-[[[(1R)-1- [(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: [MH]+ 626.0 D.3.161

Chemical Name: 6-(Acetylsulfanyl)hexanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: [MH]+ 638.9 D.3.162

Chemical Name: (Thiophene-2-sulfonyl)acetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: [MH]+ 655.0 D.3.163

Chemical Name: 4-(Acetylamino)butanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: [MH]+ 593.7 D.3.164

Chemical Name: (2Z)-3-(Propylaminocarbonyl)-2-propenamide,N-[(1S)-1-[[[(1R)-1- [(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: [MH]+ 606.1 D.3.165

Chemical Name: 3-(Octylsulfonyl)propanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: [MH]+ 699.29 D.3.166

Chemical Name: 3-(Octylsulfanyl)propanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: [MH]+ 667.35 D.3.167

Chemical Name: 2,2-Dimethylhexanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: [MH]+ 593.65 D.3.168

Chemical Name: 6-Hydroxyhexanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: [MH]+ 581.16 D.3.169

Chemical Name: 4-Oxopentanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+ 565.60D.3.170

Chemical Name: 5-Oxohexanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+ 579.17D.3.171

Chemical Name: Benzothiazole-6-carboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [immo(nitroamino)methyl]amino]butyl]Analytical Data: MS: [MH]+ 628.70 D.3.172

Chemical Name: 3-(Octyloxy)propanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: [MH]+ 651.33 D.3.173

Chemical Name: 2-(2-Oxo-pyrrolidin-1-yl)-acetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: [MH]+ 592.75 D.3.174

Chemical Name: Benzamide,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-2- hydroxypropyl]Analytical Data: MS: [MH]+ 471.47 D.3.175

Chemical Name: 2-[2-(2- Methoxyethoxy)ethoxy]acetamide,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2- hydroxypropyl] Analytical Data: MS: [MH]+527.12 D.3.176

Chemical Name: 4-Phenylbutanamide,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-l53.2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2- hydroxypropyl] Analytical Data: MS: [MH]+513.10 D.3.177

Chemical Name: (4-Methylphenoxy)acetamide,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2- hydroxypropyl] Analytical Data: MS: [MH]+515.57 D.3.178

Chemical Name: Hexanamide,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-2- hydroxypropyl]Analytical Data: MS: [MH]+ 465.40 D.3.179

Chemical Name: 4-Butylbenzamide,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-2- hydroxypropyl]Analytical Data: MS: [MH]+ 527.16 D.3.180

Chemical Name: Naphthalene-2-carboxamide,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2- hydroxypropyl] Analytical Data: MS: [MH]+521.14 D.3.181

Chemical Name: Hexanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[immo(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+ 565.33D.3.182

Chemical Name: 2-(4-Methylbenzenesulfonyl)acetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: [MH]+ 663.30 D.3.183

Chemical Name: Heptanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+ 579.34D.3.184

Chemical Name: 11-(Carbamoyl)undecanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: [MH]+ 678.44 D.3.185

Chemical Name: 2-(Benzenesulfonyl)acetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]Analytical Data: MS: [MH]+ 649.28

Further compounds prepared according to the above Example D.3 arereported in Table D-3A.

TABLE D-3A Ex # Structure Chemical Name and Analytical Data D.3.186

Chemical Name: 9-Cyanononamide, N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino] butyl] Analytical Data: MS: MH+ 632.5D.3.187

Chemical Name: 11-Cyanoundecanamide, N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino] butyl]Analytical Data: MS: MH+ 659.7; 1H-NMR (CDCl3): 7.53 (s, br, 2H); 7.36(d, br, J = 4.7 Hz, 1H); 6.88 (d, J = 8.2 Hz, 1H); 4.46 (m, 1H); 4.15(dd, J = 8.5, 1.9 Hz, 1H); 3.19 (m, 2H); 2.93 (m, 1H); 2.23 (t, J = 7.2Hz, 2H); 2.21 (m, 1H); 2.09 (t, J = 7.5, 2H); 2.04 (m, 1H); 1.88 (t, J =5.4 Hz, 1H); 1.77 (m, 1H); 1.69 (m, 1H); 1.64-1.43 (m, 9H); 1.40-1.26(m, 4H); 1.26 (s, 3H); 1.24-1.12 (m, 16H); 0.80 (d, J = 6.6, 3H); 0.79(d, J = 6.6, 3H); 0.73 (s, 3H). D.3.188

Chemical Name: 6-(Acetylamino)hexanamide, N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)- hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2- yl]-3-methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino] butyl] Analytical Data: MS: [MH]+ 622.3D.3.189

Chemical Name: 12-(1,3-Dioxo-1,3-dihydro-isoindol- 2-yl)-dodecanamide,N-[(1S)-1- [[[(1R)-1-[(3aS,4S,6S,7aR)- hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino] butyl]Analytical Data: MS: [MH]+ 794.42 D.3.190

Chemical Name: 3-[4-(2-Propyl)phenyl]propanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)- hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2- yl]-3-methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino] butyl] Analytical Data: MS: [M]H+ 641.5D.3.191

Chemical Name: 3-[4-(Ethyl)phenyl]propanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)- hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2- yl]-3-methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino] butyl] Analytical Data: MS: [M]H+ 627.7D.3.192

Chemical Name: 6-hydroxyhexanamide, N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)- hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino] butyl]Analytical Data: MS: [M]H+ 581.5

Example D.4 Naphthalene-2-sulfonamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl]-

To a solution of(2S)-2-amino-5-[[imino(nitroamino)methyl]-amino]-pentanamide,N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]-,hydrochloride salt of Example C.1 (70 mg, 0.14 mmol) in DCM (4 mL), TEA(0.04 mL, 0.31 mmol) and naphthalene-2-sulfonyl chloride (35.1 mg, 0.16mmol) were added at room temperature. After stirring overnight a secondportion of TEA (0.04 mL, 0.31 mmol) and naphthalene-2-sulfonyl chloride(35.1 mg, 0.16 mmol) was added and the reaction was allowed to stir fora further night. The reaction mixture was then washed with saturatedaqueous K₂CO₃ and the separated organic phase was concentrated todryness. The reaction crude was purified on SPE-SI normal phasecartridge to afford the title compound (64 mg, yield 70%).

NMR (CDCl₃): 8.42 (s, br, 1H); 7.96 (dd, J=7.5, 2.2 Hz, 1H); 7.95 (d,J=8.5 Hz, 1H); 7.89 (d, br, J=7.9 Hz, 1H); 7.81 (dd, J=8.8, 1.9 Hz, 1H);7.68-7.57 (m, 2H); 7.23 (s br, 2H); 6.23 (s br, 1H); 6.03 (d, J=8.5 Hz,1H); 4.19 (dd, J=9.1, 2.2 Hz, 1H); 3.92 (s, br, 1H); 3.31 (m, 2H); 2.97(m, 1H); 2.26 (m, 1H); 2.12 (m, 1H); 1.93 (t, J=5.7 Hz, 1H); 1.90-1.68(m, 6H); 1.30 (s, 3H); 1.28 (m, 1H); 1.25 (s, 3H); 1.06 (m, 4H); 0.79(s, 3H); 0.58 (d, J=9.4 Hz, 3H); 0.56 (d, J=9.4 Hz, 3H).

LC-MS 657.3, MH+, ESI POS; AQA; spray 4 kV/skimmer: 20 V/probe 250 C.

Further compounds prepared fundamentally in accordance with the aboveexperimental procedures are reported in Table D-4.

TABLE D-4 Ex # Structure Chemical Name and Analytical Data D.4.1

Chemical Name: Naphthalene-1-sulfonamide, N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino] butyl]Analytical Data: MS: MH+ 657.3 D.4.2

Chemical Name: Naphthalene-2-sulfonamide, N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino] butyl]Analytical Data: MS: MH+ 657.3; 1H-NMR (CDCl3): 8.42 (s, br, 1H); 7.96(dd, J = 7.5, 2.2 Hz, 1H); 7.95 (d, J = 8.5 Hz, 1H); 7.89 (d, br, J =7.9 Hz, 1H); 7.81 (dd, J = 8.8, 1.9 Hz, 1H); 7.68-7.57 (m, 2H); 7.23 (sbr, 2H); 6.23 (s br, 1H); 6.03 (d, J = 8.5 Hz, 1H); 4.19 (dd, J = 9.1,2.2 Hz, 1H); 3.92 (s, br, 1H); 3.31 (m, 2H); 2.97 (m, 1H); 2.26 (m, 1H);2.12 (m, 1H); 1.93 (t, J = 5.7 Hz, 1H); 1.90-1.68 (m, 6H); 1.30 (s, 3H);1.28 (m, 1H); 1.25 (s, 3H); 1.06 (m, 4H); 0.79 (s, 3H); 0.58 (d, J = 9.4Hz, 3H); 0.56 (d, J = 9.4 Hz, 3H). D.4.3

Chemical Name: Decane-1-sulfonamide, N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl] amino]butyl]Analytical Data: MS: MH+ 671.4 D.4.4

Chemical Name: Octanesulfonamide, N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl] amino]butyl]Analytical Data: MS: MH+ 643.4 D.4.5

Chemical Name: Benzenesulfonamide, N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl] amino]butyl]Analytical Data: MS: MH+ 607.3 D.4.6

Chemical Name: 4-Butoxyenzenesulfonamide, N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl] amino]butyl]Analytical Data: MS: [M + H]+ 679.5 D.4.7

Chemical Name: 4-Butyl-benzenesulfonamide, N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro- 3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino] butyl] Analytical Data: MS: [M]H+ 663.5D.4.8

Chemical Name: 4-Pentyl-benzenesulfonamide, N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl] amino]butyl]Analytical Data: MS: [M]H+ 677.3

Example D.4.9 Naphthalene-2-sulfonamide,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]

Naphthalene-2-sulfonyl chloride (144 mg, 0.637 mmol) was added to asolution of (2S)-amino-(3R)-hydroxy-butyric amide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]-carbonyl]hydrochloridesalt, of Example C.3, and NMM (0.175 ml, 1.59 mmol) in anhydrousdichloromethane, while stirring at 0° C. under nitrogen. After 6 hoursthe mixture was allowed to warm to room temperature and stirredovernight. A 10% solution of NaHCO₃ (10 ml) was added and the layerswere separated. The aqueous phase was further extracted withdichloromethane (5 ml). The organic phases were washed with a 20%solution of NaH₂PO₄, dried over sodium sulfate and concentrated. Theresidue was purified by column chromatography (Silica gel, 25 g) elutingwith a 1:1 (v/v) mixture of hexane and ethyl acetate. The product wasobtained as a white glassy solid (219 mg, 74% yield) but stillcontaining some pinanediol. A sample of that product (160 mg) wastriturated with a mixture of diethyl ether (3 ml) and hexane (3 ml)affording the pure product as a white solid (80 mg, 27% yield). M.p.147-149° C.

¹H NMR (DMSO-d6): 8.40 (1H, s); 8.28-8.22 (1H, m); 8.11 (1H, d, J=7.7);8.05 (1H, d, J=8.7); 8.01 (1H, d, J=7.8); 7.81 (1H, dd, J=8.7, 1.7);7.75 (1H, s br.); 7.72-7.61 (2H, m); 4.84 (1H, s br.); 4.03 (1H, dd,J=8.5, 1.7); 3.82-3.72 (2H, m); 2.41-2.33 (1H, m); 2.20-2.10 (1H, m);2.02-1.93 (1H, m); 1.82-1.72 (2H, m); 1.58-1.50 (1H, m); 1.36-1.24 (1H,m); 1.20 (3H, s); 1.18 (3H, s); 0.99 (3H, d, J=6.1); 0.94-0.82 (2H, m);0.77 (3H, s); 0.63 (3H, d, J=7.1); 0.61 (3H, d, J=7.1).

Example D.5(2S)-4-[[imino(nitroamino)methyl]amino]-2-[(2-naphthylmethyl)-amino]-pentanamide,N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]

A solution of(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]pentanamide,N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]-,hydrochloride salt of Example C.1 (88 mg, 0.175 mmol) in MeOH (4 mL) waspassed through a ISOLUTE PSA cartridge in order to obtain the startingmaterial as a free base. To a solution of the free base in MeOH (4 mL),2-naphtaldehyde (45 mg, 0.28 mmol) and NaCNBH₃ (18 mg, 0.28 mmol) wereadded at room temperature; AcOH was added until the pH of the solutionwas 4-5. The reaction mixture was stirred overnight, then H₂O (1 mL) wasadded and the resulting solution was concentrated; the residue,dissolved in AcOEt, was washed with brine and the organic phase wasconcentrated to dryness. Purification by silica gel flash chromatography(DCM/MeOH/NH₄OH, 97.5/2.5/0.25) of the reaction crude, afforded thedesired compound (30 mg, yield 28%).

NMR (CDCl₃+D₂O): 7.81 (m, 3H); 7.71 (s, br, 1H); 7.52-7.38 (m, 3H); 4.66(s, br, 1H); 4.27 (dd, J=8.8, 1.9 Hz, 1H); 3.91 and 3.83 (ABq, 2H);3.39-3.11 (m, 3H); 2.30 (m, 1H); 2.13 (m, 1H); 1.98-1.45 (m, 8H); 1.45(m, 2H); 1.38 (s, 3H); 1.23 (s, 3H); 1.22 (m, 1H); 0.91 (d, J=6.3 Hz,6H); 0.81 (s, 3H).

LC-MS 607.1, MH+. ESI POS; AQA; spray 4 kV/skimmer: 20 V/probe 250 C.

Further compounds prepared fundamentally in accordance with the aboveexperimental procedures are reported in Table D-5.

TABLE D-5 Ex # Structure Chemical Name and Analytical Data D.5.1

Chemical Name: (2S)-4-[[imino(nitroamino)methyl]amino]-2-[(2-naphthylmethyl)-amino]-pentanamide, N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl] Analytical Data: MS:MH+ 607.1; 1H-NMR (CDCl3 + D2O): 7.81 (m, 3H); 7.71 (s, br, 1H);7.52-7.38 (m, 3H); 4.66 (s, br, 1H); 4.27 (dd, J = 8.8, 1.9 Hz, 1H);3.91 and 3.83 (ABq, 2H); 3.39-3.11 (m, 3H); 2.30 (m, 1H); 2.13 (m, 1H);1.98-1.45 (m, 8H); 1.45 (m, 2H); 1.38 (s, 3H); 1.23 (s, 3H); 1.22 (m,1H); 0.91 (d, J = 6.3 Hz, 6H); 0.81 (s, 3H). D.5.2

Chemical Name: (2S)-4-[[imino(nitroamino)methyl]amino]-2-[(1-naphthylmethyl)-amino]-pentanamide, N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl] Analytical Data: MS:MH+ 607.2 D.5.3

Chemical Name: (2S)-4-[[imino(nitroamino)methyl]amino]-2-[undecylamino]-pentanamide, N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl] Analytical Data: MS:MH+ 621.2 D.5.4

Chemical Name: (2S)-4-[[imino(nitroamino)methyl]amino]-2-[(phenylmethyl)amino]-pentanamide, N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl] Analytical Data: MS:MH+ 557.2

Example D.6N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl]-N′-(1-naphthyl)urea

To a solution of(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-pentanamide,N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]-,hydrochloride salt of Example C.1 (50 mg, 0.10 mmol) in CH₃CN (4 mL),TEA (0.014 mL, 0.10 mmol) and naphthalene-1-isocyanate (0.014 mL, 0.10mmol) were added at room temperature. The reaction mixture was stirredfor 4 hours and then concentrated to dryness. The residue, dissolved inDCM, was washed with H₂O: the organic layer was separated and thesolvent removed under vacuum. Purification by silica gel flashchromatography (DCM 95, MeOH 5) gave the title compound as a whitepowder (60 mg, yield 94%).

NMR (CDCl₃): 8.08 (s, br, 1H); 7.98 (m, 1H); 7.79 (m, 2H); 7.57 (d,J=8.2 Hz, 1H); 7.51-7.35 (m, 4H); 7.36 (d, J=7.5 Hz, 1H); 7.17 (s, br,1H); 6.67 (d, br, J=6.6 Hz, 1H); 4.49 (m, 1H); 4.20 (dd, J=8.5, 1.9 Hz,1H); 3.39 (m, 1H); 3.20 (m, 1H); 3.04 (m, 1H); 2.26 (m, 1H); 2.08 (m,2H); 1.93 (t, J=5.6 Hz, 1H); 1.89-1.55 (m, 7H); 1.39 (m, 1H); 1.32 (s,3H); 1.31 (m, 1H); 1.21 (s, 3H); 1.20 (m, 1H); 0.85 (d, J=6.0 Hz, 6H);0.79 (s, 3H).

LC-MS 636.3, MH+. ESI POS; AQA; spray 4 kV/skimmer: 20 V/probe 250° C.

Further compounds prepared fundamentally in accordance with the aboveexperimental procedures are reported in Table D-6.

TABLE D-6 Ex # Structure Chemical Name and Analytical Data D.6.1

Chemical Name: N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]-N′-(2-naphthyl) urea Analytical Data: MS: MH+ 636.4 D.6.2

Chemical Name: N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]-N′-phenyl urea Analytical Data: MS: MH+ 586.3 D.6.3

Chemical Name: N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]-N′-heptyl urea Analytical Data: MS: MH+ 608.4 D.6.4

Chemical Name: N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]-N′-(1-naphthyl) urea Analytical Data: MS: MH+ 636.3; 1H-NMR(CDCl3): 8.08 (s, br, 1H); 7.98 (m, 1H); 7.79 (m, 2H); 7.57 (d, J = 8.2Hz, 1H); 7.51-7.35 (m, 4H); 7.36 (d, J = 7.5 Hz, 1H); 7.17 (s, br, 1H);6.67 (d, br, J = 6.6 Hz, 1H); 4.49 (m, 1H); 4.20 (dd, J = 8.5, 1.9 Hz,1H); 3.39 (m, 1H); 3.20 (m, 1H); 3.04 (m, 1H); 2.26 (m, 1H); 2.08 (m,2H); 1.93 (t, J = 5.6 Hz, 1H); 1.89-1.55 (m, 7H); 1.39 (m, 1H); 1.32 (s,3H); 1.31 (m, 1H); 1.21 (s, 3H); 1.20 (m, 1H); 0.85 (d, J = 6.0 Hz, 6H);0.79 (s, 3H). D.6.5

Chemical Name N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]-N′-undecylurea Analytical Data: MS: MH+ 664.4 D.6.6

Chemical Name: N-[(1S,2R)-1-[[[(1R)-1-[(3 aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2- hydroxypropyl]-N′-undecylurea AnalyticalData: MS: [MH]+ 564.40 D.6.7

Chemical Name: N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]-N′-[5-(ethoxycarbonyl)pentyl] urea Analytical Data: MS: [MH]+652.40 D.6.8

Chemical Name: N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl] amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]-N′-(4-butylphenyl) urea Analytical Data: MS: [M]H+ 642.5 D.6.9

Chemical Name: N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]butyl]-N′-(4-heptyloxylphenyl) urea Analytical Data: MS: [M]H+ 700.7

Example D.7 Boronic Acid,[(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[[(E)-3-(naphthalen-2-yl)prop-2-enoyl]amino]-1-oxopentyl]amino]-3-methylbutyl]-

To a suspension of PS-HOBT (1-hydroxybenzotriazole-6-sulfonamidomethylpolystyrene, 277 mg, 0.31 mmol, loading 1.12 mmol/g) in DCM (6 mL) andDMF (0.6 mL), 3-naphthalen-2-yl-acrylic acid (91.2 mg, 0.46 mmol), DIC(Diisopropylcarbodiimide, 0.22 mL, 1.40 mmol) and DIPEA (0.05 mL, 0.19mmol) were added. The suspension was shaken for 3 hours at roomtemperature and then the resin was filtered under nitrogen and washedseveral times with DMF (3×5 mL), DCM (3×5 mL), DMF (3×5 mL) and THF (3×5mL). The well dried resin was suspended in DCM (6 mL) and DMF (0.6 mL)and[(1R)-1-[[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]amino]-3-methylbutyl]-boronicacid hydrochloride salt of Example C.2 (50 mg, 0.14 mmol) and DIPEA(0.06 mL, 0.20 mmol) were added. The reaction mixture was shakenovernight at room temperature. The resin was filtered off and washedwith DMF (10 mL) and DCM (2 mL) and the solvent was concentrated todryness. Purification of the crude compound by ISOLUTE SPE-SI normalphase cartridge (DCM 1, MeOH 1), afforded the title compound (25 mg,yield 35%).

NMR (DMSO+D₂O, 343 K): 8.06 (s, 1H); 7.95 (d, J=9.0 Hz, 1H); 7.94 (m,2H); 7.72 (d, 1H); 7.61 (d, J=14.9 Hz, 1H); 7.55 (d, J=9.0 Hz, 1H); 7.55(m, 2H); 6.89 (d, J=14.9 Hz, 1H); 4.40 (m, 1H); 3.30-3.10 (m, 3H); 1.82(m, 1H); 1.73-1.53 (m, 4H); 1.50-1.32 (m, 2H); 0.87 (d, J=6.1 Hz, 3H);0.86 (d, J=6.1 Hz, 3H).

LC-MS 495.0, [M−18]H+. ESI POS; AQA; spray 5 kV/skimmer: 15 V/probe 250C.

Further compounds prepared fundamentally in accordance with the aboveexperimental procedures are reported in Table D-7.

TABLE D-7 Ex # Structure Chemical Name and Analytical Data D.7.1

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl] amino]-2-[[(2E)-3-(2-methoxyphenyl)-1-oxoprop- 2-enyl]amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: MH+ 475.0 D.7.2

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl] amino]-2-[((E)-2-methyl-3-phenylacryl)amino]- 1-oxopentyl]amino]- 3-methylbutyl]Analytical Data: MS: [M-18]H+ 458.0 D.7.3

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl] amino]-2-[(4-(4-methylphenyl)butanoyl)amino]-1- oxopentyl]amino]-3-methylbutyl]Analytical Data: MS: [M-18]H+ 474.0 D.7.4

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl] amino]-2[((2RS)-2- phenylpropanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical Data: MS: [M-18]H+ 447.2D.7.5

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl] amino]-2-[(2-(4-isopropylphenoxy)acetyl)amino]-1- oxopentyl]amino]-3-methylbutyl]Analytical Data: MS: [M-18]H+ 491.5 D.7.6

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl] amino]-2-[(5-oxo-5- phenylpentanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical Data: MS: [M-18]H+ 489.5D.7.7

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl] amino]-2-[[(4RS)-1-[(1,1-dimethylethoxy)carbonyl] piperidine-4-carbonyl]amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical Data: MS: [M-18]H+ 526.1D.7.8

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl] amino]-2-[(4- diethylaminobenzoyl)amino]-1-oxopentyl]amino]- 3-methylbutyl] Analytical Data: MS: [M-18]H+ 508.1D.7.9

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl] amino]-2-[((E)-2- methylhex-2-enoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical Data: MS: [M-18]H+ 443.0D.7.10

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl] amino]-2-[(tiophen-3-carbonyl)amino]-1-oxopentyl] amino]-3-methylbutyl] Analytical Data: MS:[M-18]H+ 425.6 D.7.11

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl] amino]-2-[(4-isopropylbenzoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical Data: MS: [M-18]H+461.3 D.7.12

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl] amino]-2-[(5-methylthiophene-2-carbonyl)amino]-1- oxopentyl]amino]-3- methylbutyl] Analytical Data:MS: [M-18]H+ 439.3 D.7.13

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl] amino]-2-[(benzoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical Data: MS: [M-18]H+ 419.4D.7.14

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]- 2-[((E)-2-butenoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical Data: MS: [M-18]H+ 383.2D.7.15

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]- 2-[((E)-penta-2,4-dienoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical Data: MS: [M-18]H+ 395.4D.7.16

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]- 2-[(3,3-dimethyl-butanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical Data: MS: [M-18]H+ 413.0D.7.17

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl] amino]-2-[[5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyl]amino]- 1-oxopentyl]amino]-3-methylbutyl]Analytical Data: MS: [M-18]H+ 547.2 D.7.18

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl] amino]-2-[(2,2-dimethylpentanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical Data: MS: [M-18]H+427.5 D.7.19

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl] amino]-2-[[4-(thiophen-2-yl)butanoyl]amino]-1- oxopentyl]amino]-3- methylbutyl] Analytical Data:MS: [M-18]H+ 467.5 D.7.20

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]- 2-[[5-(4-fluorophenyl)pentanoyl]amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical Data: MS: [M-18]H+493.4 D.7.21

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]- 2-[(2,2-dimethylhexanoyl)amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M-18]H+ 441.0D.7.22

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]- 2-[(hex-2,4-enoyl)amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M-18]H+ 409.3D.7.23

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]- 2-[[3-(thiophen-2-yl)propenoyl]amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical Data: MS: [M-18]H+451.4 D.7.24

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]- 2-[(5-cyclohexylpentanoyl)amino]-1-oxopentyl]amino]- 3-methylbutyl] Analytical Data: MS: [M-18]H+ 481.1D.7.25

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]- 2-[((3R)-3,7-dimethyloct-6-enoyl)amino]-1-oxopentyl]amino]- 3-methylbutyl] Analytical Data: MS:[M-18]H+ 467.3 D.7.26

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]- 2-[[3-[(4-methylbenzyl)sulfanyl]propanoyl]amino]-1-oxopentyl] amino]-3-methylbutyl] Analytical Data: MS:[M-18]H+ 507.0 D.7.27

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]- 2-[(4-pyrrol-1-ylbenzoyl)amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M-18]H+ 484.4D.7.28

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]- 2-[(5-fluoro-2-methoxybenzoyl)amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M-18]H+ 466.9D.7.29

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]- 2-[((2S)-2-methylbutanoyl)amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M-18]H+ 399.0D.7.30

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2- [(cyclopropanecarbonyl)amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M-18]H+ 383.0D.7.31

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]- 2-[(4-ethoxybenzoyl)amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M-18]H+ 463.5D.7.32

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]- 2-[((E)-3-(4-bromophenyl)prop-2-enoyl)amino]-1-oxopentyl]amino]- 3-methylbutyl] Analytical Data: MS:[M-18]H+ 523.6 D.7.33

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]- 2-[[(2S)-2-(6-methoxynaphthalen-2-yl)-propanoyl]amino]-1- oxopentyl]amino]-3-methylbutyl] AnalyticalData: MS: [M-18]H+ 527.5 D.7.34

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]- 2-[[1-(4-methoxyphenyl)-cyclopropanecarbonyl]amino]-1- oxopentyl]amino]-3-methylbutyl]Analytical Data: MS: [M-18]H+ 489.4 D.7.35

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]- 2-[(3-fluoro-4-methoxybenzoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical Data: MS: [M-18]H+466.9 D.7.36

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]- 2-[[(E)-3-(naphthalen-2-yl)prop-2-enoyl]amino]-1-oxopentyl]amino]- 3-methylbutyl] Analytical Data: MS:[M-18]H+ 495.0; 1H-NMR: (DMSO + D2O, 343 K): 8.06 (s, 1H); 7.95 (d, J =9.0 Hz, 1H); 7.94 (m, 2H); 7.72 (d, 1H); 7.61 (d, J = 14.9 Hz, 1H); 7.55(d, J = 9.0 Hz, 1H); 7.55 (m, 2H); 6.89 (d, J = 14.9 Hz, 1H); 4.40 (m,1H); 3.30-3.10 (m, 3H); 1.82 (m, 1H); 1.73-1.53 (m, 4H); 1.50-1.32 (m,2H); 0.87 (d, J = 6.1 Hz, 3H); 0.86 (d, J = 6.1 Hz, 3H). D.7.37

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]- 2-[(4-fluoro-3-methylbenzyl)amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M-18]H+ 451.3D.7.38

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]- 2-[[[[[(9H-fluoren-9-yl)methoxy]carbonyl]amino]butanoyl] amino]-1-oxopentyl]amino]-3- methylbutyl]Analytical Data: MS: [M-18]H+ 622.2 D.7.39

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]- 2-[(4-bromobenzoyl)amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M-18]H+ 497.1D.7.40

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]- 2-[(3-butenoyl)amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M-18]H+ 383.2 D.7.41

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]- 2-[(undecanoyl)amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M-18]H+ 483.4 D.7.42

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]- 2-[[4-(acetylamino)butanoyl]amino]-1-oxopentyl]amino]- 3-methylbutyl] Analytical Data: MS: [M-18]H+ 442.2D.7.43

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]- 2-[(6-phenylhexanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl]- Analytical Data: MS: [M-18]H+ 489.27D.7.44

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]- 2-[(5-phenylpentanoyl)amino]-1-oxopentyl]amino]-3-methylbutyl]- Analytical Data: MS: [M-18]H+ 475.23D.7.45

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]- 2-[(3-methoxypropanoyl)amino]-1-oxopentyl]amino]-3-methylbutyl]- Analytical Data: MS: [M-18]H+ 401.16D.7.46

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]- 2-[[2,2-dimethyl-3-(2-methylpropenyl)-cyclopropanecarbonyl]amino]-1- oxopentyl]amino]-3-methylbutyl]-Analytical Data: MS: [M-18]H+ 465.29 D.7.47

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]- 2-[(3-methoxycyclohexanecarbonyl)amino]-1-oxopentyl]amino]-3- methylbutyl]- Analytical Data: MS: [M-18]H+455.57 D.7.48

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]- 2-[[3-(1H-indol-3-yl)-propanoyl]amino]-1-oxopentyl]amino]- 3-methylbutyl]- Analytical Data: MS: [M-18]H+486.24 D.7.49

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]- 2[((RS)-2-cyclopent-2-enyl-acetyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical Data: MS: [M-18]H+422.99 D.7.50

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]- 2[(5-thiophen-2-yl-pentanoyl)amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M-18]H+ 481.19D.7.51

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(6-oxo-heptanoyl)amino]-1-oxopentyl] amino]-3-methylbutyl] AnalyticalData: MS: [M-18]H+ 441.24 D.7.52

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2- [(7-oxo-octanoyl)amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M-18]H+ 455.47 D.7.53

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2- [(hexanoyl)amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M-18]H+ 413.06 D.7.54

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2- [(heptanoyl)amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M-18]H+ 427.14 D.7.55

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2- [(3-octyloxy-propanoyl)amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M-18]H+ 499.17D.7.56

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2- [(benzothiazol-6-carbonyl)amino-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M-18]H+ 476.31D.7.57

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2- [(undec-2-enoyl)amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M-18]H+ 481.41 D.7.58

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]- 2-[(9-decenoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical Data: MS: [M-18]H+ 467.31D.7.59

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2- [(tetradecanoyl)amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M-18]H+ 525.10

Further compounds prepared according to the above procedure for ExampleD.7 are reported in Table D-7A.

TABLE D-7A Chemical Name and Ex # Structure Analytical Data D.7.60

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl] amino]-2-[(11-cianoundecanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical Data: MS: [M-18]H+508.5 D.7.61

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl] amino]-2-[(9-cyanononanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical Data: MS: [M-18]H+480.1

Example D.8 Decanamide,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]-

Decanoic acid (220 mg, 1.28 mmol, 1.2 eq.) was dissolved in DMF dry (15ml) at r.t., TBTU (410 mg, 1.28 mmol, 1.2 eq.) was added and theresulting solution was stirred for 10′. The mixture was cooled at 0°-5°C., NMM (0.35 ml, 3.2 mmol, 3 eq.) was added and then(2S)-amino-(3R)-hydroxy-butyric amide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]hydrochloridesalt, of Example C.3, (430 mg, 1.067 mmol, 1 eq.) was added. Thesolution was stirred for 2 h, then was poured in water (200 ml) andextracted with ethyl acetate (100 ml). The organic layer was washed withthe following solutions: citric acid 2% (20 ml), sodium bicarbonate 2%(20 ml), NaCl 2% (25 ml). The organic solution was dried over sodiumsulphate anhydrous, filtered and evaporated under reduced pressure togive 600 mg of oil that was purified by silica gel chromatography (ethylacetate/n-hexane 1/1) to give 540 mg of white solid that was suspendedovernight in diethyl ether (5 ml) and n-hexane (20 ml). The suspensionwas filtered to give 110 mg of white solid. Yield 20%.

Analytical data: m.p. 108°-110° C., TLC silica gel (n-hexane/ethylacetate 1/1 r.f. 0.33). E.A. calculated C (66.91%), H (10.26%), N(5.38%), B (2.08%). found C (66.82%), H (10.61%), N (5.35%), B (1.93%).

¹H-NMR (DMSO-d₆) δ_(H): 8.81 (1H, br); 7.68 (1H, d, J=8.80 Hz); 4.93(1H, d, J=5.2); 4.28 (1H, dd, J=8.8, 4.3); 4.05 (1H, dd, J=8.6, 1.8);3.92 (1H, m); 2.52 (1H, m); 2.20 (1H, m), 2.17 (2H, t, J=7.1); 2.00 (1H,m); 1.83 (1H, t, J=5.8); 1.78 (1H, m); 1.64 (1H, m); 1.62 (1H, m); 1.49(2H, m); 1.34 (1H, d, J=10.0); 1.31-1.17 (21H, m); 1.04 (3H, d, J=6.4);0.91-0.83 (9H, m); 0.81 (3H, s).

Further compounds prepared according to the above procedure include thefollowing:

Example D.8.1 (2S)-2-[(Benzyloxycarbonyl)amino]-4-methylpentanamide,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]-

Analytical data: TLC (CHCl₃ 9/MeOH 1, R.f. 0.63), m.p. 38°-40° C., E.A.calculated C (64.60%), H (8.54%), N (6.85%). found C (62.44%), H(8.24%), N (7.47%).

¹H NMR (DMSO-d₆) δ_(H): 8.78 (1H, br); 7.82 (1H, d, J=8.60 Hz); 7.52(1H, d, J=8.1); 7.40-7.27 (6H, m); 5.02 (2H, br s); 5.00 (1H, d, J=5.1);4.28 (1H, dd, J=8.6, J=4.2); 4.12 (1H, q, J 7.8); 4.05 (1H, dd, J=8.6,J=1.8); 3.94 (1H, m); 2.52 (1H, m); 2.19 (1H, m); 2.01 (1H, m); 1.83(1H, t, J=5.8); 1.78 (1H, m); 1.74-1.55 (5H, m); 1.46 (2H, m); 1.32 (1H,d, J=10.1); 1.24 (3H, s); 1.22 (3H, s); 1.04 (3H, d, J=6.2); 0.91-0.82(12H, m); 0.80 (3H, s).

Example D.8.210-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-decanoic-amide-N-[(1S),(2R)-2-hydroxy,1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]aminocarbonyl]-propyl]-

Analytical data: TLC (CHCl₃ 9/MeOH 1 R.f. 0.83), E.A. calculated C(66.52%), H (8.43%), N (6.37%). found C (66.76%), H (8.48%), N (6.31

¹H NMR (DMSO-d₆) δ_(H): 8.80 (1H, br); 7.85 (4H, m), 7.67 (1H, d, J=8.80Hz); 4.93 (1H, d, J=5.5), 4.28 (1H, dd, J=8.6, 4.0); 4.04 (1H, dd); 3.92(1H, m); 3.56 (2H, t, J=8.1); 2.49 (1H, m); 2.23-2.12 (3H, m); 2.00 (1H,m); 1.82 (1H, t, J=6.6); 1.78 (1H, m); 1.73-1.53 (5H, m); 1.48 (2H, m);1.33 (1H, d, J=10.1); 1.31-1.17 (20H, m); 1.03 (3H, d, J=6.2); 0.84 (6H,d, J=6.6); 0.80 (3H, s).

Further compounds prepared according to the above procedures for ExampleD.8, D.8.1 and D.8.2 are reported in Table D-8.

TABLE D-8 Ex # Structure Chemical Name D.8.3 

Chemical Name: 4-(Pyridin-3-yl)benzamide, N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S, 6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]- 2-hydroxypropyl]. Analytical Data: ¹H NMR(DMSO-d₆): 9.02 (1 H, s); 8.99 (1 H, s); 8.63 (1 H, d, J = 4.7); 8.22 (1H, d, J = 8.4); 8.17 (1 H, d, J = 8.1); 8.04 (2 H, d, J = 8.3); 7.89 (2H, d, J = 8.3); 7.53 (1 H, dd, J = 7.8, 4.8); 5.18 (1 H, d, J = 5.1);4.53 (1 H, dd, J = 8.3, 5.1); 4.11-4.01 (2 H, m); 2.60-2.53 (1 H, m);2.25-2.15 (1 H, m); 2.05-1.97 (1 H, m); 1.86-1.75 (2 H, m); 1.73-1.58 (2H, m); 1.37-1.24 (3 H, m); 1.25 (3 H, s); 1.22 (3 H, s); 1.13 (3 H, d, J= 6.2); 0.85 (6 H, d, J = 6.4); 0.81 (3 H, s). D.8.4 

Chemical Name: 2-Pyrazinecarbossamide, N- [(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- melthylbutyl]amino]carbonyl]- 2-hydroxypropyl].D.8.5 

Chemical Name: Tridecanamide, N-[(1S,2R)-1- [[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6- methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino] carbonyl]-2-hydroxypropyl]. D.8.6 

Chemical Name: 4-Phenylbenzamide, N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)- hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol- 2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]. Analytical Data: ¹H-NMR (DMSO-d6):9.04 (1 H, bs); 8.18 (1 H, d, J = 8.5); 8.00 (2 H, d, J = 8.5); 7.81 (2H, d, J = 8.4); 7.77-7.73 (2 H, m); 7.51 (2 H, t, J = 7.5); 7.43 (1 H,t, J = 7.3); 5.07 (1 H, d, J = 6.2); 4.55-4.50 (1 H, m); 4.10-4.01 (2 H,m); 2.60-2.54 (1 H, m); 2.25-2.16 (1 H, m); 2.06-1.98 (1 H, m); 1.84 (1H, t, J = 5.6); 1.82-1.76 (1 H, m); 1.74-1.60 (2 H, m); 1.35 (1 H, d, J= 10); 1.30-1.26 (2 H, m); 1.25 (3 H, s); 1.22 (3 H, s); 1.13 (3 H, d, J= 6.2); 0.87-0.83 (6 H, m); 0.81 (3 H, s). D.8.7 

Chemical Name: 2,2-Dimethydecanamide, N- [(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]- 2-hydroxypropyl].Analytical Data: ¹H-NMR (DMSO-d6): 8.93 (1 H, bs); 7.03 (1 H, d, J =8.6); 5.06 (1 H, d, J = 5.9); 4.36-4.31 (1 H, m); 4.06-4.01 (2 H, m);3.99-3.92 (1 H, m); 2.24-2.14 (1 H, m); 1.90-1.76 (2 H, m); 1.70-1.58 (2H, m); 1.50-1.42 (2 H, m); 1.38-1.32 (1 H, m); 1.28-1.20 (15 H, m);1.19-1.12 (6 H, m); 1.12-1.08 (6 H, m); 1.03 (3 H, d, J = 6.3);0.87-0.83 (9 H, m); 0.81 (3 H, s). D.8.8 

Chemical Name: (4-phenoxy)benzamide, N-[(1S,2R)-1-(1R)-1-[(3aS,4S,6S,7aR)- hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2- yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]. Analytical Data: ¹H-NMR (DMSO-d6): 9.01 (1 H, bs);8.07 (1 H, d, J = 8.5); 7.96- 7.92 (2 H, m); 7.47-7.42 (2 H, m); 7.22 (1H, t, J = 7.4); 7.11-7.06 (4 H, m); 5.04 (1 H, d, J = 6.2); 4.52-4.47 (1H, m); 4.10-3.98 (2 H, m); 2.60-2.52 (1 H, m); 2.24-2.16 (1 H, m);2.08-1.98 (1 H, m); 1.86-1.74 (2 H, m); 1.62-1.58 (2 H, m); 1.35 (1 H,t, J = 10.0); 1.30-1.24 (2 H, m); 1.23 (3 H, s); 1.22 (3 H, s); 1.10 (3H, d, J = 6.3); 0.86-0.84 (6 H, m); 0.80 (3 H, s). D.8.9 

Chemical Name: 5-Butyl-2-pyridinecarboxamide, N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro- 3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2- yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]. D.8.10

Chemical Name: 4-propoxybenzamide, N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)- hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol- 2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]. Analytical Data: ¹H NMR (DMSO-d6): 9.02 (1H, s); 7.95 (1 H, d, J = 8.6); 7.87 (2 H, d, J = 8.8); 7.02 (2 H, d, J =8.8); 5.03 (1 H, d, J = 6.2); 4.49 (1 H, dd, J = 8.4, 4.9); 4.03-3.98 (4H, m); 2.58-2.50 (1 H, m); 2.24-2.15 (1 H, m); 2.04-1.97 (1 H, m); 1.85-1.59 (7 H, m); 1.23 (3 H, s); 1.22 (3 H, s); 1.18 (2 H, t, J = 7.1);1.10 (3 H, d, J = 6.3); 0.99 (3 H, t, J = 7.4); 0.85 (3 H, d, J = 6.4);0.84 (3 H, d, J = 6.4); 0.81 (3 H, s). D.8.11

Chemical Name: 3-(3-Pyridyl)benzamide, N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S, 7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol- 2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]. Analytical Data: ¹H-NMR (DMSO-d6): 9.05-8.95(2 H, m); 8.63 (1 H, dd, J = 1.53 Hz, J = 4.76 Hz); 8.39 (1 H, J = 8.51Hz); 8.25 (1 H, m); 8.19-8.14 (1 H, m); 7.96-7.90 (2 H, m); 7.64 (1 H,t, J = 7.74 Hz); 7.57-7.51 (1 H, m); 5.053 (1 H, d, J = 6.06 Hz); 4.54(1 H, dd, J = 5.36 Hz, J = 8.43 Hz); 4.12-4.00 (2 H, m); 2.61-2.54 (1 H,m); 2.25-2.14 (1 H, m); 2.05-1.95 (2 H, m); 1.82 (1 H, t, J = 5.55 Hz);1.80- 1.74 1 H, m); 1.73-1.56 (1 H, m); 1.34 (1 H, d, J = 10.04 Hz);1.31-1.25 (2 H, m); 1.22 (6 H, d, J = 9.04 Hz); 1.14 (3 H, d, J = 6.33Hz); 0.87-0.83 (6 H, m); 0.79 (3 H, bs). D.8.12

Chemical Name: 6-Phenyl-2-pyridinecarboxamide,N-[(1S,2R)-1-[[[(1R)-1-(3aS,4S, 6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]- 2-hydroxypropyl]. Analytical Data: ¹H-NMR(DMSO-d6): 9.20-8.95 (1 H, m); 8.76 (1 H, d, J = 8.55 Hz); 8.26-8.16 (4H, m); 8.12 (1 H, t, J = 7.77 Hz); 8.02 (1 H, d, J = 7.56 Hz); 7.60-7.47(4 H, m); 5.27 (1 H, d, J = 4.97 Hz); 4.50 (1 H, dd, J = 4.22 Hz, J =8.50 Hz); 4.16-4.07 (2 H, m); 2.65-2.56 (1 H, m); 2.25-2.15 (1 H, m);2.09-1.98 (1 H, m); 1.84 (1 H, t, J = 5.62 Hz); 1.79-1.73 (1 H, m);1.73-1.66 (1 H, m); 1.66-1.59 (1 H, m); 1.40-1.26 (4 H, m); 1.23 (7 H,d, J = 10.89 Hz); 1.15-1.10 (4 H, m); 0.85 (7 H, d, J = 6.56 Hz); 0.79(1 H, bs). D.8.13

Chemical Name: 3-propoxybenzamide, N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)- hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2- yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]. Analytical Data: ¹H-NMR (DMSO-d6): 9.05-9.0 (1 H, m);8.11 (1 H, d, J = 8.49 Hz); 7.48-7.43 (2 H, m); 7.40 (1 H, t, J = 7.80Hz); 7.15-7.10 (1 H, m); 5.04 (1 H, d, J = 6.26 Hz); 4.49 (1 H, dd, J =5.15, J = 8.43 Hz); 4.10-4.05 (1 H, m); 4.05-4.01 (1 H, m); 3.99 (2 H,t, J = 6.50 Hz); 2.25-2.15 (1 H, m); 2.05-1.96 (1 H, m); 1.83 (1 H, t, J= 5.56 Hz); 1.81- 1.72 (3 H, m); 1.72-1.57 (2 H, m); 1.34 (1 H, d, J =10.06 Hz); 1.31- 1.25 (2 H, m); 1.24 (4 H, bs); 1.22 (3 H, bs); 1.10 (3H, d, J = 6.31 Hz); 1.02 (3 H, t, J = 7.40 Hz); 0.84 (6 H, dd, J = 1.84Hz, J = 6.56 Hz), 0.81 (3 H, bs). D.8.14

Chemical Name: 1-Bromonaphthalene-2-carboxamide,N-[(1S,2R)-1-[[[(1R)-1-(3aS,4S,6S, 7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol- 2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]. D.8.15

Chemical Name: 6-Bromonaphthalence-2-carboxamide,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S, 7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol- 2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]. D.8.16

Chemical Name: 3-Phenylbenzamide, N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)- hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol- 2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]. Analytical Data: ¹H-NMR (DMSO-d6): 9.03 (1H, s); 8.34 (1 H, d, J = 8.5); 8.18 (1 H, s); 7.87 (2 H, t, J = 7.1);7.75 (2 H, d, J = 7.8); 7.60 (1 H, t, J = 7.7); 7.52 (2 H, t, J = 7.6);7.42 (1 H, t, J = 7.4); 5.05 (1 H, d, J = 6.2); 4.54 (1 H, dd, J = 8.4,5.3); 4.10-4.00 (2 H, m); 2.60-2.53 (1 H, m); 2.24-2.14 (1H, m);2.05-1.97 (1 H, m); 1.82 (1 H, t, J = 5.5); 1.80-1.74 (1 H, m); 1.73-1.57 (2 H, m); 1.37-1.22 (3 H, m); 1.24 (3 H, s); 1.21 (3 H, s); 1.13 (3H, d, J = 6.2); 0.85 (3 H, d, J = 6.5); 0.84 (3 H, d, J = 6.5); 0.80 (3H, s). D.8.17

Chemical Name: 4-(2-Fluorophenyl)benzamide,N-[(1S,2R)-1-[[[(1R)-1-(3aS,4S, 6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol- 2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl].

The intermediate carboxylic acids for the synthesis of examples D.8.3,D.8.7, D.8.11, D.8.12 and D.8.13 were prepared according to literatureprocedures. Compound 2,2-dimethyldecanoic acid was prepared as describedby Roth et al. in J. Med. Chem. 1992, 35, 1609-1617. Compounds4-(3-pyridyl)benzoic acid, 3-(3-Pyridyl)benzoic acid and6-phenyl-2-pyridinecarboxilic acid were prepared according the proceduredescribed by Gong et al. in Synlett, 2000, (6), 829-831. Compound3-propoxybenzoic acid was prepared according the procedure described byJones in J. Chem. Soc. 1943, 430-432.

Example D.8.18 2-Pyrazinecarboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-carbamoylethyl]

This compound has been prepared essentially according to the aboveprocedures for Example D.8, D.8.1 and D.8.2 starting from(2S)-2-amino-3-carbamoylpropanamide,N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl];hydrochloride salt of Example C.3.

¹H-NMR (DMSO-d6): 9.20 (1H, d, J=1.29 Hz); 9.02 (1H, d, J=8.52 Hz); 8.91(1H, d, J=2.45 Hz); 8.81-8.76 (2H, m); 7.42 (1H, s); 6.95 (1H, s);5.00-4.80 (1H, m); 4.30-4.08 (1H, m); 2.85-2.72 (1H, m); 2.62-2.56 (2H,m); 2.25-2.15 (1H, m); 2.06-1.98 (1H, m); 1.84 (1H, t, J=5.54 Hz);1.81-1.76 (1H, m); 1.72-1.58 (2H, m); 1.32-1.26 (1H, m); 1.23 (8H, d,J=5.36 Hz); 0.85-0.79 (9H, m).

Example D.8.19 Decanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-carbamoylethyl]

This compound has been prepared essentially according to the aboveprocedures for Example D.8, D.8.1 and D.8.2 starting from(2S)-2-amino-3-carbamoylpropanamide,N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl];hydrochloride salt of Example C.3.

Example D.8.20 4-Butylbenzamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-carbamoylethyl]

This compound has been prepared essentially according to the aboveprocedures for Example D.8, D.8.1 and D.8.2 starting from(2S)-2-amino-3-carbamoylpropanamide,N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl];hydrochloride salt of Example C.3.

Example D.9 Decanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-[(4-methylbenzoyl)amino]ethyl]-

Decanoic acid (330 mg, 1.95 mmol, 1.2 eq.) was dissolved in DMF dry, (20ml) and TBTU (620 mg, 1.95 mmol, 1.2 eq.) was added at r.t. undernitrogen. The solution was stirred for 10′, cooled at 0°-5° C. and NMM(0.53 ml, 4.9 mmol, 3 eq.) and(2S)-2-amino-3-[(4-methylbenzoyl)amino]propanamide,N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]-,hydrochloride salt (800 mg, 1.58 mmol, 1 eq.) of Example C.4, were addedand the resulting mixture was stirred at r.t. for 3 h. The solution waspoured in water (200 ml) extracted with ethyl acetate (100 ml), washedwith solutions of citric acid 2% (50 ml), sodium bicarbonate 2% (50 ml),NaCl 2% (50 ml). The organic solution was dried over sodium sulphateanhydrous, filtered, evaporated and suspended in diethyl ether (20 ml)for 30′. The suspension was filtered and dried to give 330 mg of whitesolid. Yield 33%.

M.P.: 134° C.-136° C., TLC, silica gel, (eluent n-hexane/ethyl acetate,r.f. 0.5). E.A. calculated C (69.33%), H (9.37%), N (6.74%), B (1.73%).found C (%), H (%), N (23%), B (%).

¹H NMR (DMSO-d₆) 8.74 (1H, d, J=3.5 Hz); 8.25 (1H, t, J=5.6); 7.95 (1H,d, J=7.9); 7.71 (2H, d, J=8.1); 7.25 (2H, t, J=8.1); 4.59 (1H, m); 4.1(1H, dd, J=1.8, 8.8); 3.49 (2H, m); 2.59 (1H, m); 2.35 (3H, s); 2.20(1H, m); 2.09 (1H, t, J=7.3); 2.02 (1H, m); 1.83 (1H, t, J=5.5); 1.78(1H, m); 1.62 (2H, m); 1.44 (2H, m); 1.36-1.21 (17H, m); 1.25 (3H, s),1.22 (3H, s); 0.85 (3H, t, J=6.8); 0.80 (9H, m).

Example D.10 2-S-Decanoylamino-3-(hexanoylamino)-propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]

Decanoic acid (170 mg, 0.98 mmol, 1.2 eq.) was dissolved in DMF dry, (15ml) and TBTU (310 mg, 0.98 mmol, 1.2 eq.) was added at r.t. undernitrogen. The solution was stirred for 20′, cooled at 0°-5° C. and NMM(0.271 ml, 2.46 mmol, 2.5 eq.) and2-S-amino-3-(hexanoylamino)-propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl],hydrochloride salt, (400 mg, 0.82 mmol, 1 eq.) of Example C.5, wereadded and the resulting mixture was stirred at r.t. for 3 h. Thesolution was poured in water (150 ml) extracted with ethyl acetate (100ml), washed with solutions of citric acid 2% (50 ml), sodium bicarbonate2% (50 ml), NaCl 2% (50 ml). The organic solution was dried over sodiumsulphate anhydrous, filtered, evaporated and suspended in ethyl acetate(20 ml) for 30′. The suspension was filtered and dried to give 230 mg ofwhite solid. Yield 47%.

Analytical data: m.p. 135°-137° C., TLC silica gel (eluent hexane/ethylacetate 2/1, R.f.=0.27). E.A. calculated C (67.64%), H (10.35%), N(6.96%). found C (66.93%), H (10.29%), N (7.14%).

¹H NMR (DMSO-d₆) δ_(H): 8.67 (1H, d, J=2.9 Hz); 7.83 (1H, d, J=8.2);7.67 (1H, t, J=5.5); 4.41 (1H, m); 4.10 (1H, dd, J=1.5, 8.6); 3.25 (2H,m); 2.56 (1H, m); 2.20 (1H, m); 2.13-1.95 (5H, m); 1.84 (1H, t, J=5.5);1.78 (1H, m); 1.64 (2H, m); 1.46 (4H, m); 1.35-1.15 (27H, m); 0.84 (9H,m); 0.79 (3H, s).

Example D.11 2-S-Decanoylamino-3-(4-fluorosulfonylamino)propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]

Decanoic acid (160 mg, 0.94 mmol, 1.2 eq.) was dissolved in DMF dry, (20ml) and TBTU (300 mg, 0.94 mmol, 1.2 eq.) was added at r.t. undernitrogen. The solution was stirred for 20′, cooled at 0°-5° C. and NMM(0.259 ml, 2.36 mmol, 2.5 eq.) and2-S-amino-3-(4-fluorosulfonylamino)propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl],hydrochloride salt, (430 mg, 0.78 mmol, 1 eq.) of Example C.6, wereadded and the resulting mixture was stirred at r.t. for 2 h. Thesolution was poured in water (200 ml) extracted with ethyl acetate (100ml), washed with the following solutions: citric acid 2% (50 ml), sodiumbicarbonate 2% (50 ml), NaCl 2% (50 ml). The organic solution was driedover sodium sulphate anhydrous, filtered, evaporated and purified bysilica gel chromatography (eluent n-hexane/ethyl acetate 2/1). Thesolvent was evaporated and n-hexane was added to give 100 mg of solid.Yield 19%.

Analytical data: m.p. 83°-85° C., TLC silica gel (eluent hexane/ethylacetate 2/1, R.f.=0.53).

¹H NMR (DMSO-d₆) δ_(H): 8.45 (1H, d, J=3.8 Hz); 7.83 (3H, m); 7.63 (1H,t, J=6.2); 7.42 (2H, t, J=8.8); 4.40 (1H, m); 4.12 (1H, dd, J=1.5, 8.6);2.95 (2H, m); 2.64 (1H, m); 2.21 (1H, m); 2.17 (2H, t, J=7.3); 2.01 (1H,m); 1.83 (1H, t, J=5.5); 1.78 (1H, m); 1.62 (2H, m); 1.45 (2H, m);1.4-1.1 (23H, m); 0.87-0.8 (9H, m); 0.79 (3H, s).

Example D.122-S-Decanoylamino-3-(3,4-dimethoxyphenylacetamido)propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]

Decanoic acid (80 mg, 0.48 mmol, 1.2 eq.) was dissolved in DMF dry, (20ml) and TBTU (150 mg, 0.48 mmol, 1.2 eq.) was added at r.t. undernitrogen. The solution was stirred for 20′, cooled at 0°-5° C. and NMM(0.13 ml, 1.2 mmol, 2.5 eq.) and2-S-amino-3-(3,4-dimethoxyphenylacetamido)propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl],hydrochloride salt, (230 mg, 0.4 mmol, 1 eq.) of Example C.7, were addedand the resulting mixture was stirred at r.t. for 2 h. The solution waspoured in water (200 ml) extracted with ethyl acetate (100 ml), washedwith the following solutions: citric acid 2% (50 ml), sodium bicarbonate2% (50 ml), NaCl 2% (50 ml). The organic solution was dried over sodiumsulphate anhydrous, filtered, evaporated and purified by silica gelchromatography (eluent n-hexane/ethyl acetate 1/1). The solvent wasevaporated to give 100 mg of glassy solid. Yield 35.7%. Analytical data:TLC silica gel (eluent hexane/ethyl acetate 1/1, R.f.=0.53). E.A.calculated C (67.13%), H (9.25%), N (6.02%). found C (65.38%), H(9.20%), N (5.49).

¹H NMR (DMSO-d₆) δ_(H): 8.65 (1H, d, J=3.5 Hz); 7.84 (2H, m); 6.83 (2H,m); 6.72 (1H, dd, J=1.7, 8.1); 4.43 (1H, m); 4.10 (1H, dd, J=1.8, 8.6);3.72 (3H, s); 3.70 (3H, s); 3.30 (2H, s); 3.27 (2H, m); 2.58 (1H, m);2.19 (1H, m); 2.02 (3H, m); 1.84 (1H, t, J=5.5); 1.78 (1H, m); 1.63 (2H,m); 1.43 (2H, m); 1.35-1.15 (23H, m); 0.87-0.8 (9H, m); 0.79 (3H, s).

Example D.13 2-S-Decanoylamino-3-(phenylureido)propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]

Decanoic acid (170 mg, 0.99 mmol, 1.2 eq.) was dissolved in DMF dry, (20ml) and TBTU (310 mg, 0.99 mmol, 1.2 eq.) was added at r.t. undernitrogen. The solution was stirred for 20′, cooled at 0°-5° C. and NMM(0.27 ml, 2.4 mmol, 2.5 eq.) and 2-S-amino-3-(phenylureido)propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl],hydrochloride salt, (420 mg, 0.82 mmol, 1 eq.) of Example C.8, wereadded and the resulting mixture was stirred at 0° C. for 2 h. Thesolution was poured in water (200 ml) extracted with ethyl acetate (100ml), washed with the following solutions: citric acid 2% (50 ml), sodiumbicarbonate 2% (50 ml), NaCl 2% (50 ml). The organic solution was driedover sodium sulphate anhydrous, filtered, evaporated and suspended indiethyl ether (20 ml) for 1 h, filtered and dried under vacuum to give140 mg of white solid that was purified by silica gel chromatography(n-hexane/ethyl acetate 1/1). Yield 25%.

Analytical data: TLC silica gel (eluent hexane/ethyl acetate 1/1,R.f.=0.4).

¹H NMR (DMSO-d₆) δ_(H): 8.73 (1H, d, J=3.1 Hz); 8.64 (1H, br s); 7.97(1H, d, J=8.2); 7.36 (2H, d, J=8.1); 7.19 (2H, t, J=8.1); 6.87 (1H, t,J=8.1); 6.1 (1H, t, J=6.0); 4.44 (1H, m); 4.10 (1H, dd, J=1.8, 8.6);3.41 (1H, m); 3.22 (1H, m); 2.59 (1H, m); 2.19 (1H, m); 2.10 (2H, t,J=7.3); 2.02 (1H, m); 1.84 (1H, t, J=5.5); 1.78 (1H, m); 1.64 (2H, m);1.46 (2H, m); 1.35-1.15 (23H, m); 0.87-0.8 (9H, m); 0.79 (3H, s).

Example D.14 2-Aminoacetamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl],Hydrochloride salt

To a solution of N-Boc-Glycine (383 mg, 2.18 mmol), in anhydrousdichloromethane (20 ml), N-methylmorpholine was added (275 μl, 2.5mmol). The mixture was cooled to −15° C., then isobutyl chloroformate(286 μl, 1.2 mmol) was slowly added. After 15 minutes(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]pentanamide,N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]-hydrochloridesalt of Example C.1 (1.00 g, 2.0 mmol) and further N-methylmorpholine(275 μl, 2.5 mmol) were added. The reaction mixture was stirred at −15°C.-10° C. for 4 h, then concentrated to small volume and partitionedbetween ethyl acetate (100 ml) and water (50 ml). The aqueous phase wasfurther extracted with ethyl acetate (20 ml). The combined organicphases were dried over sodium sulfate and concentrated. The residue wastaken up with ethyl acetate (5 ml) and the solution was dropwise addedto hexane (120 ml) while stirring at room temperature. The solid wascollected by decantation and dried under vacuum (1.18 g, 95%). Part ofthis Boc-protected intermediate (1.08 g, 1.73 mmol) was dissolved in THF(15 ml), then a 4N solution of HCl in dioxane was added. After stirringfor 5 hours at room temperature the mixture was concentrated and theresidue was triturated with diethyl ether (50 ml). The resulting whitesolid was collected by filtration, washed with diethyl ether and driedunder vacuum, yielding 856 mg of the title compound (88% yield).

¹H NMR (DMSO-d6): 8.76 (1H, d, J=3.1 Hz); 8.68 (1H, d, J=8.1); 8.56 (1H,br); 8.06 (3H, m); 7.91 (2H, br); 4.43 (1H, m); 4.14 (1H, dd, J=8.6,J=1.6); 3.60 (2H, m); 3.15 (2H, br); 2.67 (1H, m); 2.23 (1H, m); 2.04(1H, m); 1.87 (1H, t, J=5.8); 1.81 (1H, m); 1.75-1.60 (3H, m); 1.52 (3H,m); 1.41-1.28 (3H, m); 1.27 (3H, s); 1.23 (3H, s); 0.86 (3H, d, J=6.4);0.84 (3H, d, J=6.4); 0.81 (3H, s).

Example D.15 3-Aminopropanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl];Hydrochloride Salt

To a solution of 3-[[(1,1-dimethylethoxy)carbonyl]amino]propanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl-]amino]butyl]-,of Example D.3.118 (42 mg, 0.075 mmol) in diethyl ether (1.0 ml), cooledat 0° C., a 10% v/v solution of hydrogen chloride in diethyl ether (2ml) was added. The mixture was stirred for 5 hours while allowing towarm to room temperature. The resulting solid was collected byfiltration, washed with diethyl ether (3×3 ml) and dried under vacuum,giving 33 mg of the title compound (76% yield).

LC-MS 538.7, MH+. ESI POS; AQA; spray 4 kV/skimmer: 20V/probe 250 C.

Further compounds prepared according to the above Example, starting fromthe corresponding Boc protected compound of Table D.3, are reported inthe following Table D-15.

TABLE D-15 Ex # Structure Chemical Name and Analytical Data D.15.1

Chemical Name: (4RS)-piperidine-4-carboxamide, N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)- hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino] butyl], HCl salt Analytical Data: MS:MH+ 578.1 D.15.2

Chemical Name: (RS)-Piperidine-2-carboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)- hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2- yl]-3-methylbulyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino] butyl]; HCl salt Analytical Data: MS:[MH]+ 578.2 D.15.3

Chemical Name: (2S)-Piperidine-2-carboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S, 7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol- 2-yl]-3-methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino] butyl]; HCl salt Analytical Data: MS:[MH]+ 578.2 D.15.4

Chemical Name: (2R)-Piperidine-2-carboxamide, N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino] butyl];HCl salt Analytical Data: MS: [MH]+ 578.8

Example D.16 Synthesis of Further Compounds

Following the procedures of Examples D.9-D.13, the following compoundscan be prepared by reaction of decanoic acid with the intermediates ofExample C.9.

D.16.1 Decanamide, N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-2-(acetamido)ethyl]-

D.16.2 Decanamide, N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-2-(9-fluorenylmethyloxycarbamoyl)ethyl]-

D.16.3 Decanamide, N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-2-(pentyl-ureido)ethyl]-

D.16.4 Decanamide, N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- mcthylbutyl]amino]carbonyl]-2-(methanesolfonamido)ethyl]-

D.16.5 Decanamide, N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-2-[(ethoxycarbonyl-succinyl]- amide)ethyl]-

D.16.6 4-Butylbenzamide, N-[(1S)-1- [[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6- methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]- 2-[(benzyloxycarbonylamide)ethyl]- ¹HNMR (DMSO-d6): 9.79 (1 H, d); 8.32 (1 H, d); 7.8 (2 H, d); 7.3 (8 H, m);5.05 (2 H, q) 4.7 (1 H, q); 4.1 (1 H, d); 3.45 (2 H, m); 2.6 (3 H, m);2.2 (1 H, m); 2.0 (1 H, m); 1.85 (2 H, m); 1.65 (4 H, m); 1.3 (5 H, m);1.25 (6 H, d) 0.9 (3 H, t); 0.80 (9 H, m). M.p. 95°-100° C.

D.16.7 4-butylbenzamide, N-[(1S)-1- [[[(1R)-1-[(3aS,aS,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6- methano-1,3,2-benzodioxaborol-2-yl-]-3-methylbutyl]amino]carbonyl]- 2-(1H-pyrazol)ethyl]-

D.16.8 Decanamide, N-[(1S)-1-[[[(1R)-1- [(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2- [(benzyloxycarbonylamide)ethyl]- ¹H NMR(DMSO-d6): 8.69 (1 H, d); 7.85 (1 H, d); 7.35 (5 H, m); 7.05 (1 H, t);5.05 (2 H, m) 4.45 (1 H, q); 4.1 (1 H, d); 3.3 (2 H, m); 2.65 (1 H, m);2.2 (1 H, m); 2.1 (3 H, m); 1.85 (2 H, m); 1.65 (2 H, m); 1.45 (2 H, m);1.25 (22 H, m); 0.8 (12 H, m)

D.16.9 4-Phenoxybenzamide, N-[(1S)-1- [[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6- methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]- 2-[(benzyloxycarbonylamide)ethyl]- ¹HNMR (DMSO-d6): 9.8 (1 H, d); 8.4 (1 H, d); 7.9 (2 H, d); 7.4 (2 H, t);7.3 (6 H, m); 7.25 (2 H, m); 7.05 (4 H, m); 5.05 (2 H, q) 4.7 (1 H, q);4.05 (1 H, d); 3.45 (2 H, m); 2.65 (1 H, m); 2.2 (1 H, m); 2.0 (1 H, m);1.80 (2 H, m); 1.65 (2 H, m); 1.3 (4 H, m); 1.25 (6 H, d) 0.8 (9 H, m).M.p. 100°-103° C.

Example D.17 4-Butylbenzamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-(aminoethyl)-hydrochlorideSalt

4-Butylbenzamide, N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-[(benzyloxycarbonylamide)ethyl]-,of Example D.16.6, (400 mg, 0.62 mmol, 1 eq.), was dissolved in1,4-dioxane (10 ml) and methanol (5 ml). To this solution, Pd/C 10% (40mg) and HCl 4N 1,4-dioxane (1.1 eq.) were added. The mixture washydrogenated at 1 bar. At the end of the reaction, Pd/C was filteredover celite, the solvent removed under reduced pressure to give a whitefoam. Yield 95%, 320 mg. Analytical data:

¹H NMR (DMSO-d6): 8.76 (1H, d); 8.55 (1H, d); 8.15 (3H, br s); 7.95 (2H,d); 7.25 (2H, d); 4.8 (1H, m); 4.2 (1H, d); 2.80 (1H, m); 2.62 (2H, t);2.23 (1H, m); 2.04 (1H, m); 1.87 (1H, t); 1.80 (1H, m); 1.75-1.50 (2H,m), (2H, m); 1.41-1.20 (6H, d), (6H, m); 1.0-0.80 (3H, d); (3H, d); (3H,s), (3H t).

Example D.182-S-(4-Butylbenzoylamino)-3-(2-pyrazinocarbonylamino)-N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]

2-Pyrazine carboxylic acid, (76 mg, 0.61 mmol, 1.1 eq.) was dissolved inDMF dry, (5 ml) and TBTU (200 mg, 0.61 mmol, 1.1 eq.) was added at r.t.under nitrogen. The solution was stirred for 15′, cooled at 0°-5° C. andNMM (0.20 ml, 1.85 mmol, 3.3 eq.) and4-butylbenzamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-(aminoethyl)-hydrochloridesalt, from Example D.17, (310 mg, 0.56 mmol, 1 eq.) were added and theresulting mixture was stirred at 25° C. for 4 h. The solution was pouredin water (100 ml) extracted with ethyl acetate (50 ml), washed with thefollowing solutions: citric acid 2% (50 ml), NaCl 2% (50 ml), sodiumbicarbonate 2% (50 ml), NaCl 2% (50 ml). The organic solution was driedover sodium sulphate anhydrous, filtered, evaporated and suspended indiethyl ether-n-hexane for 1 h, to give a white solid that was filteredand dried under vacuum to give a white powder. Yield 52%. 180 mg.

Analytical data: M.p. 70°-72° C.

¹H NMR (DMSO-d6): 9.20 (1H, s); 9.0 (1H, t); 8.85 (1H, d); 8.8 (1H, d);8.78 (1H, d); 8.60 (1H, d); 7.82 (2H, d); 7.35 (2H, d); 4.8 (1H, m); 4.1(1H, d); 3.80 (1H, m); 3.62 (1H, m); 2.82 (1H, b); 2.65 (2H, m); 2.2-2.0(2H, m); 1.80 (1H, m); 1.75-1.50 (2H, m), (2H, m); 1.41-1.20 (6H, d),(6H, m); 1.0-0.80 (3H, d); (3H, d); (3H, s), (3H t).

Example D.19 4-Butylbenzamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-[4-fluoro-benzenesulfonammide]ethyl]-

4-Butylbenzamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-[(benzyloxycarbonylamide)ethyl]-,of Example D.17, (2.75 g, 5.02 mmol, 1 eq.), was dissolved in drymethylene chloride at 0°-5° C. To this solution 4-fluorobenzenesulfonylchloride (1.07 g, 5.52 mmol, 1.1 eq.) was added and N-methylmorpholine(NMM) (1.11 g, 11.04 mmol, 2.2 eq.) was added dropwise, after fewminutes. The mixture was stirred at 0-5° C. for 30′, then at 10° C. for1 h. The solvent was removed under reduced pressure, the crude wasdissolved in Ethyl acetate and washed with a solution of citric acid 2%(50 ml) then with a solution of sodium bicarbonate 2% (50 ml) and asolution of sodium chloride 2% (50 ml). The solution was dried overanhydrous sodium sulfate and the solvent evaporated under reducedpressure. The crude was purified by silica gel chromatography (eluentethyl acetate/n-hexane 1/2), the collected fractions have beenevaporated under reduced pressure and the white solid was suspended indiethyl ether, filtered and dried under vacuum to give a white wax.Yield 60%, 2 g. Analytical data:

¹H NMR (DMSO-d6): 8.60 (1H, d); 8.30 (1H, d); 7.85 (3H, m); 7.8 (2H, d);7.38 (2H, d); 7.30 (2H, d); 4.62 (1H, m); 4.15 (1H, d); 3.25 (2H, br);2.61 (3H, m); 2.3-2.0 (1H, m); (1H, m); 1.80 (1H, m); 1.75-1.50 (2H, m),(2H, m); 1.41-1.20 (6H, d), (6H, m); 1.0-0.80 (3H, d); (3H, d); (3H, s),(3H t).

Example D.20 4-Butylbenzamide,N-[(1S)-1-[[[(1R)-1-[(3aS,aS,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl-]-3-methylbutyl]amino]carbonyl]-2-[(2,5-dimethyl-2H-pyrazole)carbonylamino]ethyl]-

4-Butylbenzamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-[(benzyloxycarbonylamide)ethyl]-,of Example D.17, (0.9 g, 1.64 mmol, 1 eq.), was dissolved in drydichloromethane (10 ml). The resulting solution was cooled to 0°<T<5° C.and N-methyl-morpholine (0.381 g, 3.78 mmol, 2.3 eq.) was added. To themixture, 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (Rn [55458-67-8])(0.286 mg, 1.8 mmol, 1.1 eq.) was added. The mixture was stirred for 1h, then the temperature was raised to 20° C. The mixture was evaporatedunder reduced pressure, suspended in ethyl acetate (50 ml), washed with2% citric acid solution (30 ml), 2% sodium bicarbonate (30 ml), 2%sodium chloride (30 ml). The organic layer was dried over anhydroussodium sulfate and evaporated under reduced pressure. The crude waspurified by silica gel chromatography (eluent Ethyl acetate/n-hexane8/2). The collected fractions were evaporated to give a white powder,that was suspended in diethyl ether and filtered to give the desiredcompound. Yield 65%, 650 mg. Rf. 0.62.

Analytical data: M.p. 62°-64° C.

¹H NMR (DMSO-d6): 8.82 (1H, d); 8.40 (2H, m); 7.85 (2H, d); 7.3 (2H, d);6.5 (1H, s); 4.8 (1H, m); 4.15 (1H, d); 3.9 (3H, s); 3.61 (2H, m); 2.65(3H, m); 2.25 (1H, m); 2.15 (3H, s); 2.0 (1H, m); 1.80 (1H, m);1.75-1.50 (4H, m), 1.41-1.20 (5H, m), (6H, m); 0.90 (3H, t); 0.8 (9H,m);

Example D.21 4-Butylbenzamide,N-[(1S)-1-[[[(1R)-1-[(3aS,aS,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl-]-3-methylbutyl]amino]carbonyl]-2-(4-methylphenyluriedosulfonylamino)ethyl]-

4-Butylbenzamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-[(benzyloxycarbonylamide)ethyl]-,of Example D.17, (0.7 g, 1.27 mmol, 1 eq.), was dissolved in dry THF (10ml), the solution was cooled at 0°-5° C. Triethylamine (0.4 ml, 1.8mmol, 2.2 eq.) and (4-methylphenyl)-ureido-sulfonylchloride (0.34 g,1.38 mmol, 1.09 eq.) of example G.1× have been added. The suspension wasstirred at 25° C. for 1 h, then was poured in a citric acid 1% solution(30 ml) and extracted with Ethyl acetate (50 ml). The organic solutionwas washed with sodium chloride 2% solution, dried over anhydrous sodiumsulfate, filtered and evaporated under reduced pressure to give a crudethat was purified by silica gel chromatography (eluent Ethylacetate/n-hexane 1/1) Rf 0.64. The collected fractions have beenevaporated and the oil was coevaporated with diethyl ether to give awhite foam. Yield 31%, 280 mg.

Analytical data: M.p. 115°-120° C.

¹H NMR (DMSO-d6): 8.80 (1H, s); 8.40 (1H, d); 7.82 (2H, d); 7.3 (2H, d);7.25 (2H, d); 7.00 (2H, d); 4.62 (1H, m); 4.15 (1H, d); 2.61 (3H, m);2.3-2.0 (3H, s); 1.80 (1H, m); 1.75 (2H, m), 1.6 (4H, m), 1.2 (13H, m);0.9 (3H, s), 0.8 (9H m).

Example D.224-Phenoxybenzamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-(3-phenyl-ureido)ethyl]-

4-Phenoxybenzamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-(amino)ethyl]-hydrochloridesalt, from example D.25.2, (1 g, 17 mmol, 1 eq.), was dissolved in drydichloromethane (30 ml) and N-methyl-morpholine (0.2 g, 18.8 mmol, 1.1eq.) was added. The solution was cooled at 0°-5° C. and phenylisocyanate(0.22 g, 17.7 mmol, 1.1 eq.) in dichloromethane (ml) was added. Themixture was stirred for 1 h at 0°-5° C. The solution was washed withsodium chloride 2% solution (50 ml), dried over anhydrous sodium sulfateand evaporated under vacuum. The crude was suspended in diethyl ether(20 ml), stirred for 2 h, filtered and dried under vacuum at 50° C. togive a white powder. Yield 74.3%, 0.84 g.

Analytical data: M.p. 143°-145° C.

¹H NMR (DMSO-d6): 8.9 (1H, d); 8.75 (1H, s); 8.59 (1H, d); 7.95 (2H, d);7.45 (2H, t); 7.35 (2H, d); 7.2 (3H, m); 7.1 (4H, m); 6.9 (1H, m); 6.25(1H, t); 4.65 (1H, m); 4.10 (1H, d); 3.65 (1H, m); 3.4 (1H, m); 2.6 (1H,m); 2.2 (1H, m); 2.1 (1H, m); 1.85 (2H, m); 1.65 (2H, m), 1.3 (3H, m);(6H, d); 0.80 (9H, t).

Example D.23 4-Butylbenzamide,N-[(1S)-1-[[[(1R)-1-[(3aS,aS,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl-]-3-methylbutyl]amino]carbonyl]-2-(4-methylphenylsulfonylureido)ethyl]-

4-Butylbenzamide, N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-(aminoethyl)-hydrochloridesalt, from Example D.17, (560 mg, 1.07 mmol, 1 eq.) was dissolved indichloromethane dry (20 ml), and the solution was cooled at 0°-5° C.N-methyl-morpholine (0.125 ml, 1.129 mmol, 1.1 eq,); and4-toluenesulfonylisocyanate (0.22 g, 1.12 mmol, 1.1 eq,) were added andthe mixture was stirred at room temperature for 2 h. The mixture waswashed with a solution of citric acid 2% (20 ml) and a sodium chloride2% solution (25 ml). The organic layer was dried over anhydrous sodiumsulfate, filtered and evaporated under reduced pressure. The crude wasdissolved in diethyl ether (40 ml) and the solvent was evaporated. Thecrude was suspended in n-hexane (20 ml), stirred for 1 h at roomtemperature, filtered and dried under vacuum at 50° C. to give a whitepowder. Yield 75.6%, 0.55 g.

Analytical data: M.p. 168°-170° C.

¹H NMR (DMSO-d6): 10.8 (1H, s); 8.75 (1H, d); 8.35 (1H, d); 7.75 (4H,m); 7.35 (5H, m); 6.65 (1H, t); 4.5 (1H, t); 4.1 (1H, d); 3.5 (1H, m);3.25 (1H, m); 2.65 (3H, m); 2.3 (3H, d); 2.2 (1H, m); 2.1 (1H, m); 1.80(2H, m); 1.65 (4H, m), 1.3 (12H, m); 0.80 (12H, m).

Example D.24 Synthesis of Further Compounds

Following the procedures of Examples D.18-D.23, the following compoundscan be prepared by reaction of the intermediates of Example D.17 or D.25with the appropriate commercially available carboxylic acids, acylhalides, sulphonyl halides, isocyanates, sulphonylisocyanates, or withthe compounds of Examples G.14, G.15 and G.16. All the obtainedcompounds have been characterized by ¹H-NMR.

TABLE D-24 D.24.1 

Chemical Name: Decanamide, N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro- 3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-2-[4-fluoro-benzenesulfonammide] ethyl]- D.24.2 

Chemical Name: Decanamide, N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro- 3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbulyl]amino]carbonyl]-2-[(4-sulfonamidophenyl)carbonyl- amido]ethyl]- Analytical Data: ¹H NMR(DMSO-d6): 8.8 (1 H, d); 8.55 (1 H, t); 8.35 (1 H, d); 7.92 (2 H, d);7.88 (2 H, d); 7.45 (2 H, s); 4.6 (1 H, t); 3.5 (2 H, m); 2.2 (1 H, m);2.1 (2 H, m); 2.05 (1 H, m); 1.8 (2 H, m); 1.6 (2 H, m); 1.45 (3 H, m);1.25 (24 H, m); 1.65 (4 H, m), 0.80 (12 H, m). M.p. 178°-181° C. D.24.3 

Chemical Name: 4-butylbenzamide, N-[(1S)-1- [[[(1R)-1-[(3aS,aS,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl-]-3-methylbutyl]amino]carbonyl]-2- (acetamido)ethyl]- Analytical Data: ¹HNMR (DMSO-d6): 8.8 (1 H, d); 8.5 (1 H, m), 8.0 (1 H, t), 7.8 (2 H, d);7.25 (2 H, d); 7.2 (2 H, t); 4.7 (1 H, q); 4.1 (1 H, d), 3.7-3.4 (2 H,m); 2.7 (2 H, t); 2.2 (1 H, m), 2.0 (1 H, m), 1.9 (1 H, t); 1.8 (3 H,s), 1.7-1.5 (4 H, m); 1.4-1.1 (10 H, m) 1.1 (1 H, t), 0.95 (3 H, t), 0.8(9 H, m). M.p. 133°-135° C. D.24.4 

Chemical Name: 4-butylbenzamide, N-[(1S)-1- [[[(1R)-1-[(3aS,aS,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl-]-3-methylbulyl]amino]carbonyl]-2- (methanesulfonamido)ethyl]- AnalyticalData: ¹H NMR (DMSO-d6): 8.8 (1 H, d); 8.5 (1 H, m), 8.0 (1 H, t), 7.8 (2H, d); 7.25 (2 H, d); 7.2 (2 H, t); 4.7 (1 H, q); 4.1 (1 H, d), 3.7-3.4(2 H, m); 2.9 (3 H, s), 2.7 (2 H, t); 2.2 (1 H, m), 2.0 (1 H, m), 1.9 (1H, t); 1.7-1.5 (4 H, m); 1.4-1.1 (10 H, m) 1.1 (1 H, t), 0.95 (3 H, t),0.8 (9 H, m). M.p. 53°-55° C. D.24.5 

Chemical Name: 4-butylbenzamide, N-[(1S)-1- [[[(1R)-1-[(3aS,aS,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl-]-3-methylbutyl]amino]carbonyl]-2- (propylureido)ethyl]- Analytical Data:¹H NMR (DMSO-d6): 8.9 (1 H, s); 8.6 (1 H, d); 7.8 (2 H, d); 7.25 (2 H,d); 6.2 (1 H, t); 6.05 (1 H, t); 4.5 (1 H, t); 4.05 (1 H, t); 3.4 (1 H,m); 2.9 (1 H, m); 2.65 (2 H, t); 2.2 (1 H, m); 2.0 (1 H, m); 1.8 (2 H,m); 1.65 (4 H, m); 1.2 (15 H, m), 0.80 (16 H, m). D.24.6 

Chemical Name: 4-butylbenzamide, N-[(1S)-1- [[[(1R)-1-[(3aS,aS,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl-]-3-methylbutyl]amino]carbonyl]-2-[(4- methylphenyl)carbonylamino]ethyl]-Analytical Data: ¹H NMR (DMSO-d6): 8.8 (1 H, d); 8.5 (2 H, m), 7.9 (2 H,d), 7.8 (2 H, d); 7.3 (2 H, d) 7.25 (2 H, d); 4.7 (1 H, q); 4.1 (1 H,d), 3.7-3.4 (2 H, m); 2.6 (3 H, m), 2.2 (1 H, m), 2.0 (1 H, m), 1.7-1.5(4 H, m); 1.4-1.1 (12 H, m) 1.1 (1 H, t), 0.95 (3 H, t), 0.8 (12 H, m).M.p. 150°-152° C. D.24.7 

Chemical Name: 4-butylbenzamide, N-[(1S)-1- [[[(1R)-1-[(3aS,aS,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl-]-3-methylbulyl]amino]carbonyl]-2- [(1,1-dimethylethoxycarbonyl)amino]ethyl]- Analytical Data: ¹H NMR (DMSO-d6): 8.8 (1 H, s); 8.25 (1H, d); 7.8 (2 H, d); 7.3 (2 H, d); 6.9 (1 H, t); 4.65 (1 H, t); 4.1 (1H, d); 2.65 (2 H, m); 2.2 (1 H, m); 2.1 (1 H, m); 1.8 (2 H, m); 1.6 (4H, m); 1.3 (20 H, m); 0.9-0.80 (12 H, m). D.24.8 

Chemical Name: 4-butylbenzamide, N-[(1S)-1- [[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbulyl]amino]carbonyl]-2- [(thien-2-ylcarbonyl)amino]ethyl]-Analytical Data: ¹H NMR (DMSO-d6): 8.8 (1 H, d); 8.5 (1 H, m), 8.0 (1 H,t), 7.80 (2 H, d); 7.7 (2 H, m); 7.3 (2 H, d); 7.2 (1 H, t); 4.7 (1 H,q); 4.1 (1 H, d), 2.2 (1 H, m), 2.0 (1 H, m), 1.9 (1 H, t); 1.7-1.5 (4H, m); 1.4-1.1 (10 H, m) 1.1 (1 H, t), 0.95 (3 H, t), 0.8 (9 H, m).D.24.9 

Chemical Name: Decanamide, N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-2-[(thien-2-ylcarbonyl)amino]ethyl]- Analytical Data: ¹H NMR (DMSO-d6):8.8 (1 H, d); 8.5 (1 H, m), 8.0 (1 H, t), 7.80 (2 H, d); 7.7 (2 H, m);7.3 (2 H, d); 7.2 (1 H, t); 4.7 (1 H, q); 4.1 (1 H, d), 3.5 (2 H, t),2.9 (1 H, m); 2.8 (1 H, m); 2.4 (4 H, m); 2.2 (1 H, m), 2.0 (1 H, m),1.9 (1 H, t); 1.7-1.5 (4 H, m); 1.4-1.1 (10 H, m) 1.1 (1 H, t), 0.95 (3H, t), 0.8 (9 H, m) .2.9 (1 H, m); 2.8 (1 H, m); 2.4 (4 H, m); 1.9 (1 H,m); 1.85 (1 H, m); 1.65 (2 H, m); 1.50 (2 H, m); 1.35 (1 H, m); 0.85 (12H, m). M.p. 110° C. D.24.10

Chemical Name: 4-butylbenzamide, N-[(1S)-1- [[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2- (hexanonylamino)ethyl]- Analytical Data:¹H NMR (DMSO-d6): 8.8 (1 H, d); 8.5 (1 H, d), 8.0 (1 H, t), 7.80 (2 H,d); 7.3 (2 H, d); 4.7 (1 H, q); 4.1 (1 H, d), 3.5 (2 H, t), 2.6 (3 H,m), 2.2 (1 H, m), 2.0 (3 H, t), 1.9-1.75 (2 H, m); 1.7-1.5 (4 H, m); 1.5(2 H, m), 1.4-1.1 (16 H, m), 0.95-0.8 (16 H, m) D.24.11

Chemical Name: 4-butylbenzamide, N-[(1S)-1- [[[(1R)-1-[3aS,aS,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano,1,3,2- benzodioxaborol-2-yl-]-3-methylbulyl]amino]carbonyl]-2- (cyclopropancarbonylamino)ethyl]-Analytical Data: ¹H NMR (DMSO-d6): 8.8 (1 H, d); 8.5 (1 H, d), 8.0 (1 H,t), 7.80 (2 H, d); 7.3 (2 H, d); 4.7 (1 H, q); 4.1 (1 H, d), 3.5 (2 H,t), 2.6 (3 H, m), ), 2.2 (1 H, m), 2.0 (1 H, m), 1.9 (1 H, t); 1.7-1.5(4 H, m); 1.4-1.1 (10 H, m) 1.1 (1 H, t), 0.95 (3 H, t), 0.8 (9 H, m),0.7 (4 H, m). D.24.12

Chemical Name: 4-Butylbenzamide, N-[(1S)-1- [[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2- (3-phenyl-ureido)ethyl]- Analytical Data:¹H NMR (DMSO-d6): 8.9 (1 H, m); 8.8 (1 H, s), 8.5 (1 H, s), 7.9 (2 H,d), 7.5 (2 H, d); 7.4 (2 H, d); 7.3 (2 H, d), 6.9 (1 H, t); 4.7 (1 H,q); 4.1 (1 H, d), 3.7-3.4 (2 H, m); 2.6 (3 H, m), 2.2 (1 H, m), 2.0 (1H, m), 1.7-1.5 (4 H, m); 1.4-1.1 (12 H, m) 1.1 (1 H, t), 0.95 (3 H, t),0.8 (9 H, m) D.24.13

Chemical Name: 4-butylbenzamide, N-[(1S)-1- [[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2- [(N-methyl-2-pyrrolylcarbonylamide)ethyl]- Analytical Data: ¹H NMR (DMSO-d6): 8.9 (1 H, d); 8.45 (1 H, d),8.05 (1 H, t), 7.8 (2 H, d), 7.3 (2 H, d); 6.9 (1 H, s); 6.7 (1 H, t),5.95 (1 H, t); 4.7 (1 H, q); 4.1 (1 H, d), 3.8 (3 H, s); 3.6 (2 H, m);2.6 (3 H, m), 2.2 (1 H, m), 2.05 (1 H, m), 1.8 (4 H, m); 1.3 (12 H, m)0.91 (3 H, t), 0.8 (9 H, m). M.p. 88°-92° C. D.24.14

Chemical Name: 4-butylbenzamide, N-[(1S)-1- [[[(1R)-1-[3aS,aS,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano,1,3,2- benzodioxaborol-2-yl-]-3-methylbulyl]amino]carbonyl]-2- [(3,4-dimethoxyphenyl)acetylamino]ethyl]- Analytical Data: ¹H NMR (DMSO-d6): 8.8 (1 H, m); 8.4(1 H, d), 8.1 (1 H, t), 7.9 (2 H, d), 7.3 (2 H, d), 6.8 (1 H, s); 6.6 (2H, t), 4.7 (1 H, q); 4.1 (1 H, d), 3.7-3.4 (2 H, m); 2.6 (3 H, m), 2.2(1 H, m), 2.0 (1 H, m), 1.7-1.5 (4 H, m); 1.4-1.1 (12 H, m), 1.1 (1 H,t), 0.95 (3 H, t), 0.8 (9 H, m). D.24.15

Chemical Name: 4-butylbenzamide, N-[(1S)-1- [[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2- (nicotinonylamino)ethyl]- AnalyticalData: ¹H NMR (DMSO-d6): 9.1 (1 H, s) 8.9 (1 H, m); 8.7 (1 H, t), 8.6 (1H, d), 8.5 (1 H, d), 8.1 (1 H, d), 7.9 (2 H, d), 7.5 (1 H, m), 7.3 (2 H,d), 4.7 (1 H, q); 4.1 (1 H, d), 3.7-3.4 (2 H, m); 2.6 (3 H, m), 2.2 (1H, m), 2.0 (1 H, m), 1.7-1.5 (4 H, m); 1.4-1.1 (12 H, m) 1.1 (1 H, t),0.95 (3 H, t), 0.8 (9 H, m). D.24.16

Chemical Name: 4-butylbenzamide, N-[(1S)-1- [[[(1R)-1-[3aS,aS,6S,7aR)-hexahydro-3a,5,5-trimethyl- 4,6-methano,1,3,2- benzodioxaborol-2-yl-]-3-methylbulyl]amino]carbonyl]- 2-[(4-sulfonylamino) benzoylamino]ethyl]-Analytical Data: ¹H NMR (DMSO-d6): 8.9 (1 H, m); 8.7 (1 H, t), 8.6 (1 H,d), 8.0 (2 H, d), 7.9 (2 H, d), 7.8 (2 H, d) ,7.5 (2 H, s), 7.3 (2 H,d), 4.7 (1 H, q); 4.1 (1 H, d), 3.7-3.4 (2 H, m); 2.6 (3 H, m), 2.2 (1H, m), 2.0 (1 H, m), 1.7-1.5 (4 H, m); 1.4-1.1 (12 H, m) 1.1 (1 H, t),0.95 (3 H, t), 0.8 (9 H, m). M.p. 145°-147° C. D.24.17

Chemical Name: 4-butylbenzamide, N-[(1S)-1- [[[(1R)-1-[3aS,aS,6S,7aR)-hexahydro-3a,5,5-trimethyl- 4,6-methano,1,3,2- benzodioxaborol-2-yl-]-3-methylbutyl]amino]carbonyl]- 2-[(1H-tertazol-5-yl-acetylamino] ethyl]-Analytical Data: ¹H NMR (DMSO-d6): 9 (1 H, s); 8.55 (1 H, d); 8.5 (1 H,br); 7.75 (2 H, d); 7.3 (2 H, t); 4.6 (1 H, t); 3.4 (2 H, m); 2.65 (2 H,m); 2.2 (1 H, m); 2.1 (1 H, m); 1.8 (2 H, m); 1.6 (4 H, m); 1.3 (14 H,m); 0.9-0.80 (12 H, m). D.24.18

Chemical Name: 4-butylbenzamide, N-[(1S)-1- [[[(1R)-1-[(3aS,aS,6S,7aR)-hexahydro-3a,5,5-trimethyl- 4,6-methano-1,3,2- benzodioxaborol-2-yl-]-3-methylbutyl]amino]carbonyl]-2- [(4-methysulfonylphenyl)carbonylamino]ethyl]- D.24.19

Chemical Name: Decanamide, N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro- 3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-2-(nicotinonylamino)ethyl]- Analytical Data: ¹H NMR (DMSO-d6): 8.95 (1 H,s); 8.75 (1 H, m); 8.7 (1 H, d); 8.55 1 H, t), 8.15 (1 H, d); 8.0 (1 H,d); 7.50 (1 H, m); 4.6 (1 H, q); 4.1 (1 H, d); 3.5 (2 H, t); 2.62 (1 H,m); 2.2 (1 H, m); 2.10 (2 H, m); 2.08 (1 H, m); 1.80 (2 H, m); 1.60 (2H, m); 1.45 (2 H, m); 1.48 (3 H, m); 1.04 (22 H, m); 0.8 (12 H, m).D.24.20

Chemical Name: 4-butylbenzamide, N-[(1S)-1- [[[(1R)-1-[(3aS,aS,6S,7aR)-hexahydro-3a,5,5-trimethyl- 4,6-methano-1,3,2- benzodioxaborol-2-yl-]-3-methylbutyl]amino]carbonyl]- 2-[(4-(2H-tetrazol-5-yl)phenyl)carbonylamino]ethyl]- D.24.21

Chemical Name: 4-butylbenzamide, N-[(1S)-1- [[[(1R)-1-[(3aS,aS,6S,7aR)-hexahydro-3a,5,5-trimethyl- 4,6-methano-1,3,2- benzodioxaborol-2-yl-]-3-methylbutyl]amino]carbonyl]- 2-[(1-isoxazol-5-yl)-carbonylamino]ethyl]- Analytical Data: ¹H NMR (DMSO-d6): 8.95 (1 H, t);8.75 (1 H, m); 8.65 (2 H, m); 8.5 (2 H, d), 7.65 (2 H, d); 7.3 (2 H, d);7.05 (1 H, s); 4.7 (1 H, q); 4.1 (1 H, d); 3.65 (2 H, m); 2.82 (1 H, s);2.65 (3 H, m); 2.2 (1 H, m); 2.10 (2 H, m); 2.08 (1 H, m); 1.80 (2 H,m); 1.60 (4 H, m); 1.25 (12 H, m); 0.85 (12 H, m). M.p. 128°-130° C.D.24.22

Chemical Name: 4-butylbenzamide, N-[(1S)-1- [[[(1R)-1-[(3aS,aS,6S,7aR)-hexahydro-3a,5,5-trimethyl- 4,6-methano-1,3,2- benzodioxaborol-2-yl-]-3-methylbutyl]amino]carbonyl]- 2-[(4-cyanophenyl) sulfonylamino]ethyl]-Analytical Data: ¹H NMR (DMSO-d6): 8.6 (1 H, d); 8.3 (1 H, d); 8.1 (1 H,t); 8.02 (2 H, d); 7.98 (2 H, d); 7.8 (2 H, d); 7,25 (2 H, d); 4.6 (1 H,t); 4.15 (1 H, d); 3.2 (2 H, m); 2.2 (1 H, m); 2.1 (1 H, m); 1.8 (2 H,m); 1.6 (4 H, m); 1.3 (12 H, m); 0.9-0.80 (12 H, m). D.24.23

Chemical Name: 4-butylbenzamide, N-[(1S)-1- [[[(1R)-1-[(3aS,aS,6S,7aR)-hexahydro-3a,5,5-trimethyl- 4,6-methano-1,3,2- benzodioxaborol-2-yl-]-3-methylbulyl]amino] carbonyl]-2-[(1-methyl- 1H-imidazole-4-)sulfonylamino]ethyl]- Analytical Data: ¹H NMR (DMSO-d6): 8.61 (1 H, d);8.25 (1 H, d); 8.1 (1 H, t); 7.8 (2 H, d); 7.74 (2 H, d); 7.55 (1 H,br); 7.3 (2 H, d); 4.6 (1 H, t); 4.15 (1 H, d); 3.25 (2 H, m); 2.65 (3H, m); 2.2 (1 H, m); 2.04 (1 H, m); 1.8 (2 H, m); 1.6 (4 H, m); 1.3 (12H, m); 0.9-0.80 (12 H, m). M.p. 69°-71° C. D.24.24

Chemical Name: 4-butylbenzamide, N-[(1S)-1- [[[(1R)-1-[(3aS,aS,6S,7aR)-hexahydro-3a,5,5-trimethyl- 4,6-methano-1,3,2- benzodioxaborol-2-yl-]-3-methylbutyl]amino]carbonyl]- 2-[(2-thiophene) sulfonylamino]ethyl]-D.24.25

Chemical Name: 4-butylbenzamide, N-[(1S)-1- [[[(1R)-1-[(3aS,aS,6S,7aR)-hexahydro-3a,5,5-trimethyl- 4,6-methano-1,3,2- benzodioxaborol-2-yl-]-3-methylbutyl]amino]carbonyl]- 2-(6-morpholin-4- nicotinoylamino)ethyl]-D.24.26

Chemical Name: 4-butylbenzamide, N-[(1S)-1- [[[(1R)-1-[(3aS,aS,6S,7aR)-hexahydro-3a,5,5-trimethyl- 4,6-methano-1,3,2- benzodioxaborol-2-yl-]-3-methylbutyl]amino] carbonyl]-2-(2-pyridin-4-thiazolecarbonylamino)ethyl]- D.24.27

Chemical Name: 4-butylbenzamide, N-[(1S)-1- [[[(1R)-1-[(3aS,aS,6S,7aR)-hexahydro-3a,5,5-trimethyl- 4,6-methano-1,3,2- benzodioxaborol-2-yl-]-3-methylbutyl]amino]carbonyl]- 2-(4-methylphenyluriedo-sulfonylamino)ethyl]- Analytical Data: ¹H NMR (DMSO-d6): 10 (1 H, br);8.8 (1 H, s); 8.4 (2 H, d); 7.8 (2 H, d); 7.3 (2 H, d); 7.25 (2 H, d);4.6 (1 H, t); 4.2 (1 H, d); 2.65 (3 H, m); 2.2 (4 H, m); 2.0 (1 H, m);1.8 (2 H, m); 1.6 (4 H, m); 1.3 (12 H, m); 0.9-0.80 (12 H, m). D.24.28

Chemical Name: 4-phenoxybenzamide, N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)- hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2- [(benzyloxycarbonylamide) ethyl]-Analytical Data: ¹H NMR (DMSO-d6): 8.78 (1 H, br); 8.4 (1 H, d); 7.9 (2,d); 7.45 (2 H, t); 7.3 (6 H, m); 7.21 (2 H, m); 7.05 (4 H, m); 5.0 (2 H,q); 4.7 (1 H, t); 4.1 (1 H, d); 3.4 (2 H, m); 2.6 (1 H, m); 2.2 (4 H,m); 2.0 (1 H, m); 1.8 (2 H, m); 1.65 (2 H, m); 1.3 (9 H, m); 0.9-0.80 (9H, m). M.p. 100°-103° C. D.24.29

Chemical Name: 4-phenoxybenzamide, N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)- hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-2-[4-fluoro- benzenesulfonammide]ethyl]- Analytical Data: ¹H NMR(DMSO-d6): 8.6 (1H, br); 8.35 (1 H, d); 7.9 (5 H, m); 7.45 (4 H, m); 7.2(1 H, m); 7.05 (4 H, m); 4.6 (1 H, q); 4.1 (1 H, d); 3.1 (2 H, m); 2.6(1 H, m); 2.2 (4 H, m); 2.0 (1 H, m); 1.8 (2 H, m); 1.65 (2 H, m); 1.3(9 H, m); 0.9-0.80 (9 H, m). M.p. 90°-93° C. D.24.30

Chemical Name: 4-phenoxybenzamide, N-[(1S)-1-[[[(1R)-1-[(3aS,aS,6S,7aR)- hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl-]-3-methylbutyl]amino]carbonyl]-2- [(2,5-dimethyl-2H-pyrazole)carbonylamino]ethyl]- Analytical Data: ¹H NMR (DMSO-d6): 8.9 (1 H, br);8.55 (1 H, d); 8.48 (1 H, m); 7.9 (2 H, m); 7.48 (2 H, m); 7.2 (1 H, m);7.05 (4 H, m); 6.55 (1 H, s); 4.75 (1 H, q); 4.1(1 H, d); 3.6 (2 H, m);2.2 (4 H, m); 2.1 (3 H, s); 2.0 (1 H, m); 1.8 (2 H, m); 1.65 (2 H, m);1.25 (9 H, m); 0.8 (9 H, m). M.p. 100°-103° C. D.24.31

Chemical Name: 4-phenoxybenzamide, N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)- hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-2-(4-phenylbenzoylamino)ethyl]- Analytical Data: ¹H NMR (DMSO-d6): 8.85(1 H, br); 8.55 (2 H, m); 7.9 (4 H, d); 7.75 (4 H, m); 7.48 (5 H, m);7.2 (1 H, t); 7.05 (4 H, m); 4.8 (1 H, q); 4.1 (1 H, d); 3.7 (2 H, m);2.65 (1 H, m); 2.2 (1 H, m); 2.0 (1 H, m); 1.8 (2 H, m); 1.6 (2 H, m);1.25 (9 H, m); 0.8 (9 H, m). M.p. 150°-152° C. D.24.32

Chemical Name: 4-butylbenzamide, N-[(1S)-1- [[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl- 4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2- (4-phenylbenzoylamino)ethyl]- AnalyticalData: ¹H NMR (DMSO-d6): 8.85 (1 H, br); 8.6 (1 H, m); 8.5 (1 H, d); 7.9(2 H, m); 7.75 (5 H, m); 7.5 (2 H, t); 7.4 (1 H, m); 7.3 (2 H, m); 4.8(1 H, q); 4.1 (1 H, d); 3.7 (2 H, m); 2.6 (3 H, m); 2.2 (1 H, m); 2.0 (1H, m); 1.8 (2 H, m); 1.6 (4 H, m); 1.25 (9 H, m); 0.8 (12 H, m). M.p.195°-198° C. D.24.33

Chemical Name: 4-butylbenzamide, N-[(1S)-1- [[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl- 4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2- (3-phenylpropynoylamino)ethyl]-Analytical Data: ¹H NMR (DMSO-d6): 8.85 (1 H, m); 8.7 (1 H, m); 8.42 (1,d); 7.8 (2 H, m); 7.5 (5 H, m); 7.3 (3 H, m); 4.7 (1 H, q); 4.1 (1 H,d); 3.55 (2 H, m); 2.85 (2, m); 2.65 (4 H, m); 2.2 (1 H, m); 2.0 (1 H,m); 1.8 (2 H, m); 1.6 (6 H, m); 1.25 (12 H, m); 0.8 (12 H, m). M.p.118°-120° C. D.24.34

Chemical Name: 4-butylbenzamide, N-[(1S)-1- [[[(1R)-1-[(3aS,aS,6S,7aR)-hexahydro-3a,5,5-trimethyl- 4,6-methano-1,3,2- benzodioxaborol-2-yl-]-3-methylbutyl]amino]carbonyl]- 2-(2-hydroxy-3-nicotinoylamino) ethyl]-D.24.35

Chemical Name: 4-butylbenzamide, N-[(1S)-1- [[[(1R)-1-[(3aS,aS,6S,7aR)-hexahydro-3a,5,5-trimethyl- 4,6-methano-1,3,2- benzodioxaborol-2-yl-]-3-methylbutyl]amino]carbonyl]- 2-(D-piroglutamoylamino)ethyl]- AnalyticalData: ¹H NMR (DMSO-d6): 9.85 (1 H, d); 8.3 (1 H, d); 8.1 (1 H, t); 7.8(3 H, m); 7.3 (2 H, d); 4.7 (1 H, t); 4.15 (1 H, d); 3.9 (1 H, m); 3.5(2 H, m); 2.65 (3 H, m); 2.2 (2 H, m); 2.0 (3 H, m); 1.8 (3 H, m); 1.6(4 H, m); 1.3 (11 H, m); 0.9-0.80 (12 H, m). D.24.36

Chemical Name: 4-butylbenzamide, N-[(1S)-1- [[[(1R)-1-[(3aS,aS,6S,7aR)-hexahydro-3a,5,5-trimethyl- 4,6-methano-1,3,2- benzodioxaborol-2-yl-]-3-methylbutyl]amino]carbonyl]- 2-(1-methanesulfonyl-piperidine-4-carbonylamino) ethyl]- Analytical Data: ¹H NMR (DMSO-d6):9.9 (1 H, d); 8.4 (1 H, d); 8.0 (1 H, t); 7.75 (2 H, d); 7.3 (2 H, d);4.68 (1 H, q); 4.15 (1 H, d); 3.5 (4 H, m); 2.8 (3 H, s); 2.65 (3, m);2.2 (2 H, m); 2.0 (1 H, m); 1.9-1.5 (10 H, m); 1.3 (12 H, m); 0.9-0.80(12 H, m). M.p. 170°-172° C. D.24.37

Chemical Name: Decanamide, N-[(1S)-1- [[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl- 4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2- (3-phenyl-ureido)ethyl]- D.24.38

Chemical Name: Decanamide, N-[(1S)-1- [[[(1R)-1-[(3aS,aS,6S,7aR)-hexahydro-3a,5,5-trimethyl- 4,6-methano-1,3,2- benzodioxaborol-2-yl-]-3-methylbutyl]amino]carbonyl]-2- (acetamido)ethyl]-

Example D.25 Synthesis of Further Compounds

Following the procedures of Example D17, the following compounds can beprepared starting from the compounds of Example D.16.8 and D.16.9.

TABLE D-25 Chemical Name and Ex # Structure Analytical Data D.25.1

Chemical Name: Decanamide, N-[(1S)-1-[[[(1R)-1-[(3aS,aS,6S,7aR)-hexahydro- 3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl-]- 3-methylbutyl]amino]carbonyl]-2-amino]ethyl]-hydrochloride salt Analytical Data: ¹H NMR (DMSO-d6): 8.4(1H, d); 8.25 (1H, d); 8.15 (3H, br s); 4.58 (1H, m); 4.2 (1H, m); 3.1 (H, m); 2.9 (1H, m); 2.8 (1H, m); 2.4 (4H, m); 1.9 (1H, m); 1.85 (1H, m);1.65 (2H, m); 1.50 (2H, m); 1.35 (1H, m); 0.85 (12H, m). D.25.2

Chemical Name: 4-phenoxybenzamide, N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexa- hydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol- 2-yl]-3-methylbutyl]amino]carbonyl]-2-(amino)ethyl]- hydrochloride salt Analytical Data: ¹H NMR(DMSO-d6): 8.72 (1H, d); 8.54 (1H, d); 7.45 (2H, t); 7.22 (1H, t); 7.05(4H, m); 4.8 (1H, m); 4.21 (1H, d); 3.25 (1H, m); 3.15 (1H, m); 2.8 (1H,m); 2.25 (1H, m); 2.05 (1H, m); 1.9 (1H, t); 1.82 (1H, m); 1.65 (2H, m);1.28 (3H, s); 1.22 (3H, s); 0.85 (9H, m).

Example D.26 4-Butylbenzamide,N-[(1R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-[(4-methylbenzoyl)amino]ethyl]-

Following the same procedures used for the preparation of the compoundof Example D.17, the intermediate 4-butylbenzamide,N-[(1R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-(aminoethyl)-hydrochloridesalt is prepared using D-asparagine as starting material. This latterintermediate is then reacted with 4-methylbenzoic acid following theprocedure described in Example D.18 to give the title compound.

¹H NMR (MeOD-d4): 8.88 (2H, d); 8.45 (2H, m); 7.8 (2H, d); 7.7 (2H, d);7.35 (2H, m); 7.25 (2H, d); 4.75 (1H, m); 4.1 (1H, d); 3.8 (1H, m); 3.65(2H, m); 2.65 (3H, m); 2.2 (1H, m); 2.1 (1H, m); 1.8 (2H, m); 1.6 (4H,m); 1.3-1.1 (2H, m); 0.9-0.80 (14H, m).

Example E.1 Boronic Acid,[(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(2-naphthoyl)amino]-1-oxopentyl]amino]-3-methylbutyl]-

A mixture of naphthalene-2-carboxamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]-amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl]-of Example D.1.1 (564 mg, 0.90 mmol), 2-methylpropylboronic acid (222mg, 2.19 mmol) and 4N hydrogen chloride dioxane solution (225 μl) in a40:60 heterogeneous mixture of methanol:hexane (10 ml) was stirred atroom temperature for 4 hours. Hexane (4 ml) was added, the mixture wasstirred for a while, then the hexane layer was removed. Fresh hexane (5ml) and 2-methylpropylboronic acid (100 mg, 0.99 mmol) were added andthe mixture was stirred at room temperature for 3 hours. The hexanelayer was removed and the methanol phase was washed with hexane (2×5ml). The residue obtained upon concentration of the methanol phase waspurified by silica gel column chromatography eluting with ethyl acetatefirst, then with 40:40:20 acetone:methanol:hexane mixture. The productwas redissolved in a mixture of ethyl acetate (250 ml) and methanol (6ml) and the organic phase was washed with water (2×25 ml), dried oversodium sulfate and concentrated. The residue was dried under vacuum at80° C. for 3 hours affording the product as a white solid (280 mg, 64%yield). M.p. 170-190° C.

¹H NMR (DMSO-d₆): 8.76 (1H, m); 8.51 (2H, br); 8.09-7.09 (5H, m); 7.88(2H, br); 7.60 (2H, br); 4.67 (1H, m); 3.17 (2H, m); 2.58 (1H, m); 1.81(2H, m); 1.56 (3H, m); 1.38-1.11 (4H, m); 0.83 (1H, m); 0.81 (1H, m);0.74 (3H, d, J=6.4); 0.74 (3H, d, J=6.4).

El. Anal. Calculated: C 54.33% H 6.43% N 17.28% B 2.22% Found C 54.87% H6.64% N 17.00% B 2.12%

Further compounds prepared fundamentally in accordance with the aboveexperimental procedures are reported in Table E-1.

TABLE E-1 Ex # Structure Chemical Name and Analytical Data E.1.1

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[((2E)-3-ethoxycarbonyl-1-oxoprop-2-enyl)amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: ¹H-NMR (MeOH-d4): 7.07(1H, d, J = 15.6 Hz); 6.74 (1H, d, J = 15.6 Hz); 4.64 (1H, dd, J = 6.3,8.1); 4.25 (2H, q, J = 7.1); 2.75 (1H, t, J = 7.4); 2.0-1.6 (5H, m);1.34 (2H, m); 1.31 (3H, t, J = 7.1); 0.92 (6H, d, J = 6.6). E.1.2

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(2-pyrazine-carbonyl)amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data:1H-NMR (DMSO-d6): 9.18 (1H, br); 8.96 (1H, d, J = 8.2; 8.87 (1H, d, J =2.4 Hz); 8.76 (2H, m); 8.51 (1H, br); 8.3-7.5 (2H, br); 4.63 (1H, m);3.13 (2H, m); 2.53 (1H, m); 1.9-1.1 (7H, m); 0.73 (6H, d, J = 6.6).E.1.3

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(4-butyl-benzoyl)amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: 1H-NMR(DMSO-d6): 8.68 (1H, d, J = 2.5 Hz); 8.51 (1H, br); 8.48 (1H, d, J = 7.8Hz); 8.3-7.5 (2H, br); 7.80 (2H, d, J = 8.1); 7.27 (2H, d, J = 8.1 Hz);4.59 (1H, m); 3.15 (2H, m); 2.61 (2H, t, J = 7.7); 2.54 (1H, m); 1.9-1.1(11H, m); 0.89 (3H, t, J = 7.3); 0.77 (3H, t, J = 6.8); 0.74 (6H, d, J =6.6). E.1.4

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(2-naphthoyl)amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: 1H-NMR(DMSO-d6): 8.77 (1H, br); 8.76 (1H, d, J = 8.0); 8.51 (1H, br); 8.50(1H, s); 8.0 (4H, m); 8.3- 7.5 (2H, br); 7.6 (2H, m); 4.67 (1H, m); 3.17(2H, m); 2.57 (1H, m); 1.9-1.1 (7H, m); 0.73 (6H, d, J = 6.6). E.1.5

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(3-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-propylamino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: 1H-NMR(DMSO-d6): 8.59 (1H, br); 8.43 (1H, br); 8.27 (1H, d, J = 7.9 Hz); 7.82(4H, m); 8.2-7.5 (2H, br); 4.31 (1H, m); 3.77 (2H, m); 3.08 (2H, m);2.51 (3H, m); 1.7-1.1 (7H, m); 0.78 (6H, m). E.1.6

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[[2-(2-methoxyethoxy)acetyl]amino]-1-oxopentyl]amino]- 3-methylbutyl], HCl saltAnalytical Data: 1H-NMR (MeOH-d4): 4.65 (1H, dd, J = 6.1, 8.6 Hz); 4.04(2H, s); 3.70 (2H, m); 3.60 (2H, t, J = 4.04) 3.42 (3H, s); 3.30 (2H, t,J = 6.9); 2.75 (1H, t, J = 7.5); 2.0-1.6 (5H, m); 1.34 (2H, m); 0.92(6H, d, J = 6.6). E.1.7

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(2-butoxyacetyl)amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: 1H-NMR(MeOH-d4): 4.65 (1H, dd, J = 6.1, 8.6 Hz), 3.98 (2H, s); 3.54 (2H, t, J= 6.6); 3.28 (2H, t, J = 6.9); 2.77 (1H, t, J = 7.6); 2.0-1.3 (11H, m);0.95 (3H, t, J = 7.58); 0.92 (6H, d, J = 6.6). E.1.8

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[[2-[2-(2-methoxyethoxy)ethoxy]acetyl]amino]-1- oxopentyl]amino]-3-methylbutyl]Analytical Data: 1H-NMR (MeOH-d4): 4.66 (1H, dd, J = 6.0, 8.8 Hz); 4.06(2H, AB q, J = 15.7); 3.7 (6H, m); 3.58 (2H, m); 3.37 (3H, s); 3.29 (2H,t, J = 6.9); 2.75 (1H, t, J = 7.7); 2.0-1.6 (5H, m); 1.34 (2H, m); 0.92(6H, d, J = 6.6). E.1.9

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[[2-(acetylamino)acetyl]amino]-1-oxopentyl] amino]-3-methylbutyl], HCl saltAnalytical Data: 1H-NMR (MeOH-d4): 4.61 (1H, dd, J = 5.7, 8.9 Hz); 3.86(2H, s); 3.37 (3H, s); 3.30 (2H, t, J = 7.0); 2.75 (1H, t, J = 7.7);2.01 (3H, s); 2.0-1.6 (5H, m); 1.33 (2H, m); 0.92 (6H, d, J = 6.6).E.1.10

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[[4-(methoxycarbonyl)butanoyl]amino]-1- oxopentyl]amino]-3-methylbutyl]Analytical Data: ¹H NMR (DMSO-d6): 8.50 (1H, br); 8.44 (1H, d, J = 5.6Hz); 8.17 (1H, d, J = 7.5); 7.92 (2H, br); 4.37 (1H, m); 3.58 (3H, s);3.14 (2H, m); 2.57 (1H, m); 2.30 (2H, t, J = 7.3); 2.19 (2H, t, J =7.5); 1.75 (2H, quint, J = 7.3); 1.71 (1H, br); 1.64-1.39 (4H, br); 1.23(2H, m); 0.86 (2H, m); 0.82 (3H, d, J = 6.4); 0.81 (3H, d, J = 6.4).E.1.11

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(2-(naphthalen-2-yloxy)acetyl]amino]-1- oxopentyl]amino]-3-methylbutyl]Analytical Data: ¹H NMR (DMSO-d6): 8.81 (1H, br); 8.51 (1H, br); 8.40(1H, d, J = 7.5 Hz); 7.88 (2H, br); 7.83 (2H, m); 7.75 (1H, m); 7.44(1H, m); 7.35 (1H, m); 7.26 (2H, m); 4.69 (2H, m); 4.51 (1H, m); 3.12(2H, m); 2.60 (1H, m); 1.78 (1H, m); 1.73-1.39 (3H, m); 1.39- 1.11 (3H,m); 0.80 (6H, m). E.1.12

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(3-thiophen-2-yl-propanoyl)amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: 1HNMR (DMSO-d6): 8.65 (1H, br); 8.49 (1H, br); 8.20 (1H, d, J = 8.2 Hz);7.86 (2H, br); 7.27 (1H, dd, J = 4.9, J = 0.9); 6.91 (1H, dd, J = 5.1, J= 3.4); 6.84 (1H, m); 4.38 (1H, m); 3.11 (2H, m); 3.02 (2H, m); 2.56(1H, m); 2.50 (2H, m); 1.69 (1H, m); 1.64-1.35 (4H, m); 1.27 (1H, m);1.20 (1H, m); 0.82 (3H, d, J = 6.4); 0.81 (3H, d, J = 6.4). E.1.13

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[2-(2-chlorophenyl)acetyl]amino]-3-methylbutyl] HCl salt Analytical Data: ¹HNMR (DMSO-d6): 8.69 (1H, br); 8.51 (1H, br); 8.41 (1H, d, J = 7.9 Hz);7.87 (2H, br); 7.40 (1H, m); 7.32 (1H, m); 7.26 (2H, m); 4.42 (1H, m);3.66 (2H, m); 3.14 (2H, m); 2.60 (1H, m); 1.73 (1H, m); 1.68- 1.40 (4H,m); 1.26 (2H, m); 0.83 (3H, d, J = 6.4); 0.82 (3H, d, J = 6.4). E.1.14

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(1-oxo-4-(1-butylpiperidin-4-yl)butyl)amino]-1- oxopentyl]amino]-3-methylbutyl]Analytical Data: ¹H NMR (DMSO-d6): 8.60 (1H, br); 8.50 (1H, br); 8.10(1H, br); 8.00 (2H, br); 4.36 (1H, m); 3.13 (2H, br); 2.86 (2H, br);2.50 (1H, m); 2.27 (1H, br); 2.11 (2H, m); 1.76-1.34 (11H, m); 1.34-0.98(11H, m); 0.87 (3H, t, J = 7.1 Hz), 0.82 (3H, d, J = 6.4); 0.81 (3H, d,J = 6.4). E.1.15

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(1-octanesulfonyl)amino]-1-oxopentyl]amino]-3- methylbutyl], HCl saltAnalytical Data: ¹H NMR (DMSO-d6): 8.80 (1H, br); 8.50 (1H, br); 7.87(2H, br); 7.52 (1H, d, J = 8.6 Hz); 3.92 (1H, m); 3.15 (2H, m); 2.94(2H, t, J = 7.7); 2.62 (1H, m); 1.75-1.43 (7H, m); 1.38-1.31 (4H, m);1.24 (8H, s); 0.92-0.75 (9H, m). E.1.16

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-[(4-methylbenzoyl)amino]-2-[(decanoylamino)]-1-oxopropyl]amino]-3-methylbutyl] Analytical Data: ¹H NMR (CD3OD): 7.73(2H, d, J = 8.0 Hz); 7.28 (2H, d, J = 8.0); 4.78 (1H, t, J = 6.5); 3.82(1H, dd, J = 6.9, 13.5); 3.61 (1H, dd, J = 6.9, 13.5); 2.74 (1H, m);2.39 (3H, s); 2.24 (2H, t, J = 7.4); 1.6-1.15 (17H, m); 0.89 (6H, m);0.80 (3H, d, J = 6.5). E.1.17

Chemical Name: Boronic acid, [(1R)-1-[[(2S,3R)-3-hydroxy-2-[(decanoyl)amino]-1-oxobutyl]amino]-3-methylbutyl] Analytical Data: ¹HNMR (DMSO-d6): 8.58 (1H, br); 7.70 (1H, d, J = 8.6 Hz), 4.93 (1H, br);4.31 (1H, dd, J = 4.0, 8.6); 3.96 (1H, m); 2.56 (1H, m); 2.18 (2H, m);1.60 (1H, m); 1.49 (2H, m); 1.35-1.15 (14H, m); 1.03 (3H, d, J = 6.4);0.83 (9H, m). E.1.18

Chemical Name: Boronic acid, [(1R)-1-[[(2S,3R)-3-hydroxy-2-[[10-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-decanoyl]amino]-1-oxobutyl]amino]-3-methylbutyl] Analytical Data: ¹H NMR(DMSO-d6): 8.55 (1H, br); 7.84 (4H, m); 7.69 (1H, d, J = 8.4 Hz), 4.94(1H, d, J = 5.4); 4.30 (1H, dd, J = 4.0, 8.6); 3.95 (1H, m); 3.55 (2H,m); 2.55 (1H, m); 2.17 (2H, m); 1.65-1.35 (5H, m); 1.3- 1.1 (12H, m);1.02 (3H, d, J = 6.4); 0.83 (9H, m).

Further compounds prepared according to the above procedure for ExampleE.1 are reported in Table E-1A.

TABLE E-1A Ex # Structure Chemical Name and Analytical Data E.1.19

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[((RS)-10-cyano-2-cyclopentydecanoyl)amino]-1- oxopentyl]amino]-3-methylbutyl]Analytical Data: 1H-NMR (MeOH-d4): 4.57 (1 H, m); 3.29 (2 H, m); 3.20 (2H, m); 2.76 (1 H, t, J = 7.5Hz); 2.43 (2 H, t, J = 7.1); 2.05 (1 H, m);2.0-1.1 (11 H, m); 0.93 (6 H, d, J = 6.6). E.1.20

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(10-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxodecyl]-)amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: 1H-NMR(MeOH-d4): 7.82 (4 H, m); 4.52 (1 H, m); 3.66 (2 H, t, J = 7.3); 3.27 (2H, m); 2.75 (1 H, m); 2.24 (2 H, t, J = 7.3 Hz); 1.9-1.2 (20 H, m); 0.91(6 H, d, J = 6.6). E.1.21

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(2-cyclopentyl-10-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxodecyl]-)amino]-1- oxopentyl]amino]-3-methylbutyl]Analytical Data: 1H-NMR (MeOH-d4): 7.82 (4 H, m); 4.57 (1 H, m); 3.66 (2H, t, J = 7.3); 3.28 (2 H, m); 2.75 (1 H, m); 2.05 (1 H, m); 2.0-1.1 (30H, m); 0.91 (6 H, two d, J = 6.6). E.1.22

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[[7-(methoxycarbonyl)heptanoyl]amino]-1- oxopentyl]amino]-3-methylbutyl]Analytical Data: ¹H NMR (DMSO-d6): 8.60 (1 H, d, J = 8.4 Hz); 8.50 (1 H,br); 8.06 (1 H, d, J = 7.9); 7.92 (2 H, br); 4.36 (1 H, m); 3.58 (3 H,s); 3.13 (2 H, m); 2.55 (1 H, m); 2.28 (2 H, t, J = 7.5); 2.12 (2 H, m);1.69 (1 H, m); 1.49 (7 H, m); 1.24 (7 H, m); 0.81 (6 H, m).

Further compounds prepared according to the above procedure for ExampleE.1 are reported in Table E-1B.

TABLE E-1B Ex # Structure Chemical Name and Analytical Data E.1.23

Chemical Name: Boronic acid, [(1R)-1-[[(2S,3R)-3-hydroxy-2-[(4-phenylbutanoyl)amino]-1-oxobutyl]amino]-3- methylbutyl]. AnalyticalData: ¹H NMR (MeOH-d4): 7.29-7.13 (5 H, m); 4.53 (1 H, d, J = 3.9);4.21-4.14 (1 H, m); 2.72 (1 H, d, J = 7.6); 2.65 (2 H, t, J = 7.6); 2.34(2 H, t, J = 7.5); 2.10-2.89 (2 H, m); 1.70-1.59 (1 H, m); 1.37-1.27 (2H, m); 1.21 (3 H, d, J = 6.4); 0.94-0.89 (6 H, m). E.1.24

Chemical Name: Boronic acid, [(1R)-1-[[(2S,3R)-3-hydroxy-2-[(undecylaminocarbonyl)amino]-1-oxobutyl]amino]-3- methylbutyl].Analytical Data: ¹H NMR (MeOH-d4): 4.43 (1 H, d, J = 2.9); 4.27-4.20 (1H, m); 3.16 (2 H, t, J = 6.9); 2.74 (1 H, t, J = 7.6); 1.76- 1.66 (1 H,m); 1.58-1.46 (3 H, m); 1.42-1.30 (26 H, m); 1.25 (3 H, d, J = 6.4).E.1.25

Chemical Name: Boronic acid, [(1R)-1-[[(2S,3R)-3-hydroxy-2-[(1-Bromo-2-naphthoyl)amino]-1-oxobutyl]amino]-3- methylbutyl]. AnalyticalData: ¹H NMR (MeOH-d4): 8.37 (1 H, d, J = 8.52); 7.99 (2 H, dd, J = 8.2,J = 13.0); 7.75-7.60 (2 H, m); 4.82 (1 H, d, J = 4.19); 4.31-4.23 (1 H,m); 2.81 (1 H, dd, J = 6.10, J = 9.14); 1.77-1.64 (1 H, m); 1.48-1.38 (2H, m); 1.36 (3 H, d, J = 6.38); 1.0-0.9 (6 H, m). E.1.26

Chemical Name: Boronic acid, [(1R)-1-[[(2S,3R)-3-hydroxy-2-[(6-Bromo-2-naphthoyl)amino]-1-oxobutyl]amino]-3- methylbutyl]. AnalyticalData: ¹H NMR (MeOH-d4): 8.49 (1 H, s); 8.17 (1 H, d, J = 1.4); 7.99 (1H, dd, J = 1.65, J = 8.66); 7.95 (2 H, dd, J = 2.70, J = 8.62); 7.69 (1H, dd, J = 1.90, J = 8.77); 4.81 (1 H, d, J = 4.26); 4.38-4.30 (1 H, m);2.77 (1 H, t, J = 7.63); 1.71- 1.59 (1 H, m); 1.40-1.33 (2 H, m); 1.31(3 H, d, J = 6.39); 0.94-0.90 (6 H, m).

Further compounds prepared according to the above procedure for ExampleE.1 are reported in Table E-1C. starting from the compounds of ExampleD.8.19 and D.8.20.

TABLE E-1C Ex # Structure Chemical Name and Analytical Data E.1.27

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-carbamoyl-2-[(decanoyl)amino]-1-oxopropyl]amino]-3-methylbutyl] Analytical Data:1H-NMR (MeOH-d4): 4.76 (1 H, t, J = 6.0); 2.58-2.52 (3 H, m); 2.14-2.09(2 H, m); 1.64-1.52 (1 H, m); 1.51- 1.40 (2 H, m); 1.30-1.12 (14 H, m);0.84-0.80 (9 H, m). E.1.28

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-carbamoyl-2-[4-butyl(benzoyl)amino]-1-oxopropyl]amino]-3- methylbutyl] Analytical Data:1H-NMR (MeOH-d4): 7.78 (2 H, d, J = 8.24 Hz); 7.32 (2 H, d, J = 8.22Hz); 5.16 (1 H, T, J = 6.52); 2.91 (2 H, dd, J = 2.09 Hz, J = 6.53 Hz);2.78 (1 H, t, J = 7.59 Hz); 2.74- 2.66 (2 H, m); 1.72-1.60 (3 H, m);1.44-1.30 (5 H, m); 1.00-0.9 (9 H, m).

Further compounds prepared according to the above procedure for ExampleE.1 are reported in Table E-1D. starting from the compounds of ExampleD.2.9 and D.2.10.

TABLE E-1D Ex # Structure Chemical Name and Analytical Data E.1.29

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-2-[(decanoyl)amino]-1-oxo-5-ureido-pentyl]amino]-3-methylbutyl] Analytical Data: 1H-NMR(DMSO-d6): 8.56 (1 H, s); 8.07 (1 H, d, J = 8.03 Hz); 5.96 (1 H, t, J =5.18 Hz); 5.38 (2 H, s); 4.42-4.20 (1 H, m); 3.01-2.85 (2 H, m);2.65-2.40 (1 H, m); 2.25-2.00 (2 H, m); 1.70-1.52 (2 H, m); 1.52-1.40 (3H, m); 1.40-1.10 (16 H, m); 0.90-0.75 (9 H, m). E.1.30

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-2-[(4-butylbenzoyl)amino]-1-oxo-5-ureido-pentyl]amino]-3-methylbutyl] Analytical Data: 1H-NMR(MeOH-d4 + DMSO-d6): 7.80 (2 H, d, J = 8.08 Hz); 7.28 (2 H, d, J = 8.16Hz); 4.58 (1 H, t, J = 7.41 Hz); 3.00 (2 H, t, J = 6.72 Hz); 2.63 (2 H,t, J = 7.64 Hz); 1.82- 1.74 (2 H, m); 1.68-1.52 (4 H, m); 1.52-1.36 (2H, m); 1.34-1.26 (2 H, m); 1.21 (2 H, t, J = 7.23 Hz); 0.89 (3 H, t, J =7.35 Hz); 0.84 (6 H, d, J = 6.55 Hz).

Example E.2 Boronic Acid,[(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(decanoyl)amino]-1-oxopentyl]amino]-3-methylbutyl]

Decanamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl]-of Example D.1 (77 mg, 0.12 mmol), was dissolved in Et₂O (1 mL) andHC137% (2 mL) was added carefully at 0° C. The reaction mixture wasallowed to warm to room temperature and to shake overnight. The mixturewas concentrated to dryness and the residue, dissolved in MeOH (1 mL),was passed through ISOLUTE PSA cartridge, and washed with MeOH. Thesolvent was evaporated and the reaction crude product was purified withISOLUTE SPE-DIOL cartridges (DCM:MeOH 1:1) to afford the title compound(19 mg, yield 33%).

NMR (DMSO+D₂O, 343 K): 4.20 (m, 1H); 3.13 (m, 2H); 3.05 (m, 1H); 2.10(t, J=6.2 Hz, 2H); 1.69 (m, 1H); 1.53-1.40 (m, 4H); 1.39-1.20 (m, 14H);0.84 (m, 9H).

LC-MS 468.9, MH+. ESI POS; AQA; spray 4 kV/skimmer: 20V/probe 250° C.

Further compounds prepared fundamentally in accordance with the aboveexperimental procedures are reported in Table E-2.

TABLE E-2 Ex # Structure Chemical Name and Analytical Data E.2.1

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(1-oxodecyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical Data: MS:MH+ 468.9; 1H-NMR: (DMSO + D20, 343 K): 4.20 (m, 1 H); 3.13 (m, 2 H);3.05 (m, 1 H); 2.10 (t, J = 6.2 Hz, 2 H); 1.69 (m, 1 H); 1.53-1.40 (m, 4H); 1.39-1.20 (m, 14 H); 0.84 (m, 9 H). E.2.2

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(octanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical Data:MS: [M - 18]H+ 441.4 E.2.3

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(1-phenylcyclopentanecarbnyl)amino]-1- oxopentyl]amino]-3-methylbutyl]Analytical Data: MS: [M - 18]H+ 487.0 E.2.4

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[((2R)-2-phenylbutanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] AnalyticalData: MS: [M - 18]H+ 461.2 E.2.5

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[[4-(1,1-Dimethylethyl)cyclohexanecarbonyl]amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M - 18]H+ 481.1E.2.6

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(trans-4-pentylcyclohexanecarbonyl)amino]-1- oxopentyl]amino]-3-methylbutyl]Analytical Data: MS: [M - 18]H+ 495.4 E.2.7

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(4-phenylbutanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] AnalyticalData: MS: [M - 18]H+ 461.4 E.2.8

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(4-(1,1-dimethylethyl)benzoyl)amino]-1-oxopentyl]amino]- 3-methylbutyl]Analytical Data: MS: [M - 18]H+ 475.1 E.2.9

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(nonanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical Data:MS: [M - 18]H+ 455.1 E.2.10

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(2-thiophenecarbonyl)amino]-1-oxopentyl]amino]-3- methylbutyl] AnalyticalData: MS: [M - 18]H+ 425.3 E.2.11

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(2,3-difluorobenzoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] AnalyticalData: MS: [M - 18]H+ 455.0 E.2.12

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(dodecanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical Data:MS: [M - 18]H+ 497.2 E.2.13

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[[2-(2-iodophenyl)acetyl]amino]-1-oxopentyl]amino]-3- methylbutyl] AnalyticalData: MS: [M - 18]H+ 558.9 E.2.14

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2- [(cyclohexanecarbonyl)amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M - 18]H+ 425.0E.2.15

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(2-methylbenzoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical Data:MS: [M - 18]H+ 433.0 E.2.16

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[((2S)-2-phenylpropanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] AnalyticalData: MS: [M - 18]H+ 447.3 E.2.17

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(2,2-dimethylbutanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] AnalyticalData: MS: [M - 18]H+ 413.3 E.2.18

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(quinoline-2-carbonyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical Data: MS:[M - 18]H+ 470.0 E.2.19

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(non-2-enoyl)amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M -18]H+ 453.1 E.2.20

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(2-methylcyclohexanecarbonyl)amino]-1- oxopentyl]amino]-3-methylbutyl]Analytical Data: MS: [M - 18]H+ 439.4 E.2.21

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(hept-2-enoyl)amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M -18]H+ 425.4 E.2.22

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[[2-(3,4-dimethylphenoxy)acetyl]amino]-1- oxopentyl]amino]-3-methylbutyl]Analytical Data: MS: [M - 18]H+ 477.3 E.2.23

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[((RS)-4-ethyloctanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical Data:MS: [M - 18]H+ 469.5 E.2.24

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(hexahydro-2,5-methanopentalene-3a(1H)-carbonyl)amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M - 18]H+ 463.5E.2.25

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(bicyclo[2.2.1]heptane-2-carbonyl)amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M - 18]H+ 437.4E.2.26

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(5-methylhexanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] AnalyticalData: MS: [M - 18]H+ 427.0 E.2.27

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(2,4-dimethylthiazole-5-carbonyl)amino]-1- oxopentyl]amino]-3-methylbutyl]Analytical Data: MS: [M - 18]H+ 454.3 E.2.28

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(furan-3-carbonyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical Data: MS:[M - 18]H+ 408.8 E.2.29

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(2-cycloheptylacetyl)amino]-1-oxopentyl]amino]-3- methylbutyl] AnalyticalData: MS: [M - 18]H+ 453.2 E.2.30

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(1-methylcyclopropanecarbonyl)amino]-1- oxopentyl]amino]-3-methylbutyl]Analytical Data: MS: [M - 18]H+397.2 E.2.31

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(3-methylbutanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] AnalyticalData: MS: [M - 18]H+ 399.4 E.2.32

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(3-phenylpropanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] AnalyticalData: MS: [M - 18]H+ 447.3 E.2.33

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[[(E)-3-(3-methylphenyl)acryl]amino]-1-oxopentyl]amino]-3- methylbutyl] AnalyticalData: MS: [M - 18]H+ 459.5 E.2.34

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(2-adamantan-1-ylacetyl)amino]-1-oxopentyl] 3-methylbutyl] Analytical Data:MS: [M - 18]H+ 491.2 E.2.35

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[immo(nitroamino)methyl]amino]-2-[((RS)-2-methylbutanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] AnalyticalData: MS: [M - 18]H+ 398.9 E.2.36

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(2-phenylacetyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical Data:MS: [M - 18]H+ 433.4 E.2.37

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[[2-(4-methoxyphenyl)acetyl]amino]-1-oxopentyl]amino]- 3-methylbutyl]Analytical Data: MS: [M - 18]H+ 463.5 E.2.38

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[[2-(4-bromophenyl)acetyl]amino]-1-oxopentyl]amino]-3- methylbutyl] AnalyticalData: MS: [M - 18]H+511.3 E.2.39

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[((RS)-4-methyloctanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] AnalyticalData: MS: [M - 18]H+ 455.0 E.2.40

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(2-fluoro-5-methylbenzoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical Data:MS: [M - 18]H+ 451.4 E.2.41

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[[2-(bicyclo[2.2.1]hept-2-yl)acetyl]amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M - 18]H+ 451.0E.2.42

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(4-phenoxybutanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] AnalyticalData: MS: [M - 18]H+ 477.4 E.2.43

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(2-pyridinecarbonyl)ammo]-1-oxopentyl]amino]-3- methylbutyl] AnalyticalData: MS: [M - 18]H+ 419.9 E.2.44

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(3-pyridinecarbonyl)amino]-1-oxopentyl]amino]-3- methylbutyl] AnalyticalData: MS: [M - 18]H+ 420.3 E.2.45

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(tridecanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical Data:MS: [M - 18]H+ 511.6 E.2.46

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(8-phenyloctanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] AnalyticalData: MS: [M - 18]H+ 517.3 E.2.47

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[[4-(4-methanesulfonylphenyl)-4-oxobutanoyl]amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M - 18]H+ 553.3E.2.48

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[[3-(naphthalen-2-ylsulfanyl)-propanoyl]amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M - 18]H+ 529.3E.2.49

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[[2-[(phenylmethyl)sulfanyl]acetyl]amino]-1- oxopentyl]amino]-3-methylbutyl]Analytical Data: MS: [M - 18]H+ 479.5 E.2.50

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(3-Methylsulfanylpropanoyl)amino]-1- oxopentyl]amino]-3-methylbutyl]Analytical Data: MS: [M - 18]H+ 416.9 E.2.51

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[((2S)-1-acetylpyrrolidine-2-carbonyl)amino]-1- oxopentyl]amino]-3-methylbutyl]Analytical Data: MS: [M - 18]H+ 454.1 E.2.52

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[[trans-3-(2-bromophenyl)acryl]amino]-1-oxopentyl]amino]-3- methylbutyl] AnalyticalData: MS: [M - 18]H+ 523.0 E.2.53

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[[2-(tetrazol-1-yl)acetyl]amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical Data:MS: [M - 18]H+ 425.0 E.2.54

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[[2-(pyrimidin-2-ylsulfanyl)acetyl]amino]-1- oxopentyl]amino]-3-methylbutyl]Analytical Data: MS: [M - 18]H+ 467.0 E.2.55

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[[2-(4-ethylphenoxy)acetyl]amino]-1-oxopentyl]amino]-3- methylbutyl] AnalyticalData: MS: [M - 18]H+ 476.9 E.2.56

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[[2-(2,5-dimethylphenyl)acetyl]amino]-1-oxopentyl]amino]- 3-methylbutyl]Analytical Data: MS: [M - 18]H+ 461.4 E.2.57

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(8-oxo-8-phenyloctanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] AnalyticalData: MS: [M - 18]H+ 531.0 E.2.58

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[[2-(2-naphthylsulfanyl)acetyl]amino]-1- oxopentyl]amino]-3-methylbutyl]Analytical Data: MS: [M - 18]H+ 515.6 E.2.59

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[[(RS)-2-cyclopentylhexanoyl]amino]-1-oxopentyl]amino]- 3-methylbutyl] AnalyticalData: MS: [M - 18]H+ 481.1 E.2.60

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[[3-(4-methylphenyl)acryl]amino]-1-oxopentyl]amino]-3- methylbutyl] AnalyticalData: MS: [M - 18]H+ 459.0 E.2.61

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[[4-(4-methoxyphenyl)-butanoyl]amino]-1- oxopentyl]amino]-3-methylbutyl]Analytical Data: MS: [M - 18]H+ 491.6 E.2.62

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(2-thiophen-3-yl-acetyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical Data:MS: [M - 18]H+ 438.9 E.2.63

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[[2- (dimethylamino)acetyl]amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M - 18]H+ 400.2E.2.64

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[[5-oxo-5-(thiophen-3-yl)pentanoyl]amino]-1- oxopentyl]amino]-3-methylbutyl]Analytical Data: MS: [M - 18]H+ 494.9 E.2.65

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(acetyl)amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: MS:[M - 18]H+ 357.2 E.2.66

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(2-ethylsulfanylacetyl)amino]-1-oxopentyl]amino]-3- methylbutyl] AnalyticalData: MS: [M - 18]H+ 417.4 E.2.67

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(10-hydroxydecanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] AnalyticalData: MS: [M - 2H2O]H+ 467.0 E.2.68

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(2-methylsulfanylacetyl)amino]-1-oxopentyl]amino]- 3-methylbutyl]Analytical Data: MS: [M - 18]H+ 402.9 E.2.69

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[[(thiophene-2-sulfonyl)acetyl]amino]-1-oxopentyl]amino]-3- methylbutyl] AnalyticalData: MS: [M - 18]H+ 503.1 E.2.70

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[[3-(benzenesulfonyl)propanoyl]amino]-1- oxopentyl]amino]-3-methylbutyl]Analytical Data: MS: [M - 18]H+ 510.9 E.2.71

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[[(RS)-tetrahydrofuran-3-carbonyl]amino]-1- oxopentyl]amino]-3-methylbutyl]Analytical Data: MS: [M - 18]H+ 413.2 E.2.72

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2- [(naphthalene-1-sulfonyl)amino]-1-oxopentyl]amino]-3-methylbutyl]- Analytical Data: MS: [M - 18]H+ 505.23E.2.73

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2- [(naphthalene-2-sulfonyl)amino]-1-oxopentyl]amino]-3-methylbutyl]- Analytical Data: MS: [M - 18]H+ 505.49

Further compounds prepared according to the above procedure for ExampleE.2 are reported in Table E-2A.

TABLE E-2A Ex # Structure Chemical Name and Analytical Data E.2.75

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[[6- (acetylamino)hexanoyl]amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M - 18]H+ 470.2E.2.76

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[[(RS)-2-(4-chlorophenyl)propanoyl]amino]-1- oxopcntyl]amino]-3-methylbutyl]Analytical Data: MS: [M - 18]H+ 481.1 E.2.77

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[[2-(4-bromophenoxy)acetyl]amino]-1-oxopentyl]amino]- 3-methylbutyl] AnalyticalData: MS: [M - 18]H+ 524.1 E.2.78

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[[3-(4-ethylphenyl)propanoyl]amino]-1- oxopentyl]amino]-3-methylbutyl]Analytical Data: MS: [M - 18]H+ 475.2 E.2.79

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[3-[4-(heptyloxy)phenyl]-ureido]-1-oxopentyl]amino]-3- methylbutyl] AnalyticalData: MS: [M - 18]H+ 548.3 E.2.80

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(5-oxohexanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical Data:MS: [M - 18]H+ 427.2 E.2.81

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[[(2RS)-1-[(1,1-dimethylethoxy)carbonyl]piperidine-2-carbonyl]amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical Data: MS:[M - 18]H+ 526.2

Example E.3 Boronic Acid,[(1R)-1-[[(2S,3R)-3-hydroxy-2-[(4-butylbenzoyl)amino]-1-oxobutyl]amino]-3-methylbutyl]

A mixture of 4-butylbenzamide,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]-carbonyl]-2-hydroxypropyl]-of Example D.3.179 (1.38 g, 2.63 mmol), 2-methylpropylboronic acid (0.75g, 7.37 mmol) and 2N aqueous hydrochloric acid (2 ml) in a heterogeneousmixture of methanol (20 ml) and hexane (20 ml) was stirred at roomtemperature for 16 hours. The mixture was diluted with methanol (20 ml)and hexane (20 ml) then the hexane layer was removed. Ethyl acetate (50ml) was added to the methanol layer which was then concentrated. Theresidue was taken up with ethyl acetate and the mixture wasconcentrated. This step was repeated (2-3 times) until an amorphouswhite solid was obtained. The solid was then triturated with diethylether (10-15 ml) and the surnatant was removed by decantation. This stepwas repeated 4 times. After a further trituration with diethyl ether (15ml) the white solid was collected by filtration and dried under vacuumat room temperature (0.724 g, 70% yield).

¹H NMR (MeOH-d4): 7.83 (2H, d, J=8.2); 7.34 (2H, d, J=8.2); 4.77 (1H, d,J=6.4); 4.36-4.28 (1H, m); 2.77 (1H, t, J=7.6); 2.71 (2H, t, J=7.6);1.72-1.58 (3H, m); 1.46-1.32 (4H, m); 1.29 (3H, d, J=6.4); 0.97 (3H, t,J=7.34); 0.94 (6H, dd, J=1.1, 6.6)

Further compounds prepared according to the above procedure for ExampleE.3 are reported in Table E-3.

TABLE E-3 Ex # Structure Chemical Name and Analytical Data E.3.1

Chemical Name: Boronic acid, [(1R)-1-[[(2S,3R)-3-hydroxy-2-[(2-naphthoyl)amino]-1-oxobutyl]amino]-3-methylbutyl]. Analytical Data: ¹HNMR (MeOH-d4): 8.51 (1 H, s); 8.10-7.95 (4 H, m); 7.66-7.58 (1 H, m);4.84 (1 H, d, J = 4.1); 4.42-4.33 (1 H, m); 2.77 (1 H, t, J = 7.6);1.75-1.62 (1 H, m); 1.41-1.36 (2 H, m); 1.34 (3 H, d, J = 6.4); 0.94 (6H, d, J = 6.5). E.3.2

Chemical Name: Boronic acid, [(1R)-1-[[(2S,3R)-3-hydroxy-2-[(p-tolyloxyacetamide]-1-oxobutyl]amino]-3-methylbutyl]. Analytical Data: ¹HNMR (MeOH-d4): 7.14 (2 H, d, J = 8.5); 6.92 (2 H, d, J = 8.6); 4.63-4.59(3 H, m); 4.31-4.24 (1 H, m); 2.75 (1 H, t, J = 7.5); 1.72-1.60 (1 H,m); 1.38-1.33 (2 H, m); 1.31 (3 H, s); 1.17 (3 H, d, J = 6.4); 0.95-0.92(6 H, m). E.3.3

Chemical Name: Boronic acid, [(1R)-1-[[(2S,3R)-3-hydroxy-2-[(tridecanoyl)amino]-1-oxobutyl]amino]-3- methylbutyl]. Analytical Data:M.p 97-116° C. ¹H NMR (MeOH-d4): 4.55 (1 H, d, J = 3.9); 4.23-4.16 (1 H,m); 2.73 (1 H, t, J = 7.6); 2.36-2.30 (2 H, m); 1.73-1.60 (3 H, m);1.40-1.26 (20 H, m); 1.22 (3 H, d, J = 6.4); 0.97-0.90 (9 H, m). E.3.4

Chemical Name: Boronic acid, [(1R)-1-[[(2S,3R)-3-hydroxy-2-[(naphthalene-2-sulfonyl)amino]-1-oxobutyl]amino]-3- methylbutyl].Analytical Data: ¹H NMR (MeOH-d4): 8.44 (1 H, s); 8.04 (2 H, d, J =8.6); 7.98 (1 H, d, J = 7.9); 7.87 (1 H, d, J = 8.7); 7.71-7.61 (2 H,m); 4.10-4.02 (2 H, m); 2.36 (1 H, dd, J= 6.5, 8.7); 1.40- 1.26 (1 H,m); 1.12 (3 H, d, J = 5.9); 1.07-0.87 (2 H, m); 0.74 (3 H, d, J = 6.6);0.72 (3 H, d, J = 6.6). E.3.5

Chemical Name: Boronic acid, [(1R)-1-[[(2S,3R)-3-hydroxy-2-[(4-phenylbenzoyl)amino]-1-oxobutyl]amino]-3- methylbutyl]. Analytical Data:Mp 200-208° C. ¹H NMR (MeOH-d4): 8.00 (2 H, d, J = 8.4); 7.79 (2 H, d, J= 8.4); 7.70 (2 H, d, J = 7.3); 7.49 (2 H, t, J = 7.5); 7.41 (1 H, t, J= 7.3); 4.80 (1 H, d, J = 4.1); 4.38-4.31 (1 H, m); 2.78 (1 H, t, J =7.6); 1.73-1.62 (1 H, m); 1.41-1.35 (2 H, m); 1.31 (3 H, d, J = 6.4);0.94 (6 H, d, J = 6.5). E.3.6

Chemical Name: Boronic acid, [(1R)-1-[[(2S,3R)-3-hydroxy-2- [(2,2dimethyl-decanoyl)amino]-1-oxobutyl]amino]-3- methylbutyl]. AnalyticalData: ¹H NMR (MeOH-d4): 4.40 (1 H, m); 4.05-3.95 (1 H, m) 1.65-1.55 (1H, m); 1.50-1.40 (2 H, m); 1.25-1.15 (14 H, m); 1.10 (6 H, d, J = 8.8);1.06 (3 H, d, J = 6.3); 0.82-0.88 (9 H, m). E.3.7

Chemical Name: Boronic acid, [(1R)-1-[[(2S,3R)-3-hydroxy-2-[(4-Phenoxybenzoyl)amino]-1-oxobutyl]amino]-3- methylbutyl]. AnalyticalData: ¹H NMR (DMSO-d6+ MeOH-d4): 7.90 (2 H, d, J = 8.7); 7.38 (2 H, t, J= 7.9); 7.16 (1 H, t, J = 7.4); 7.02 (4 H, t, J = 8.6); 4.53 (1 H, d, J= 4.83); 4.10-3.95 (2 H, m); 2.53- 2.44 (1 H, m); 1.62-1.48 (1 H, m);1.22-1.49 (2 H, m); 1.09 (3 H, d, J = 6.35); 0.83-0.76 (6 H, m). E.3.8

Chemical Name: Boronic acid, [(1R)-1-[[(2S,3R)-3-hydroxy-2-[[4-(1-propoxy )butylbenzoyl]amino]-1-oxobutyl]amino]-3- methylbutyl].Analytical Data: ¹H NMR (MeOH-d4): 7.88 (2 H, d, J = 8.9); 7.02 (2 H, d,J = 8.9); 4.76 (1 H, d, J = 4.0); 4.32 (1 H, dq, J = 4.2, 6.4); 4.03 (2H, t, J = 6.5); 2.76 (1 H, t, J = 7.6); 1.89-1.79 (2 H, m); 1.72-1.60 (1H, m); 1.36 (2 H, t, J = 6.9); 1.28 (3 H, d, J = 6.4); 1.08 (3 H, t, J =7.4); 0.93 (1 H, dd, J = 1.8, 6.6) E.3.9

Chemical Name: Boronic acid, [(1R)-1-[[(2S,3R)-3-hydroxy-2-[(3-pyridin-3-yl-benzoyl)amino]-1-oxobutyl]amino]-3- methylbutyl],hydrochloride salt. Analytical Data: ¹H NMR (MeOH-d4): 8.90 (1 H, s);8.58 (1 H, d, J = 4.26); 8.22 (1 H, t, J = 1.59); 8.21-8.16 (1 H, m);7.97 (1 H, m); 7.93-7.89 (1 H, m); 7.66 (1 H, t, J = 7.78); 7.60- 7.54(1 H, m); 4.80 (1 H, d, J = 4.41); 4.38-4.28 (1 H, m); 2.77 (1 H, t, J =7.63); 1.71-1.60 (1 H, m); 1.39-1.33 (2 H, m); 1.29 (3 H, d, J = 6.38);0.95-0.90 (6 H, m). E.3.10

Chemical Name: Boronic acid, [(1R)-1-[[(2S,3R)-3-hydroxy-2-[(3-propoxy-benzoyl)amino]-1-oxobutyl]amino]-3- methylbutyl]. AnalyticalData: ¹H NMR (MeOH-d4): 7.49-7.44 (2 H, m); 7.41 (1 H, t, J = 7.82);7.18-7.12 (1 H, m); 4.76 (1 H, d, J = 4.21); 4.36- 4.27 (1 H, m); 4.02(2 H, t, J = 6.45); 2.77 (1 H, t, J = 7.61); 1.90-1.79 (2 H, m);1.72-1.60 (1 H, m); 1.40-1.34 (2 H, m); 1.29 (3 H, t, J = 6.39); 1.08 (3H, t, J = 7.42); 0.94 (6 H, d, J = 6.48). E.3.11

Chemical Name: Boronic acid, [(1R)-1-[[(2S,3R)-3-hydioxy-2-[(3-phenylbenzoyl)amino]-1-oxobutyl]amino]-3- methylbutyl]. Analytical Data:¹H NMR (MeOH-d4): 8.18 (1 H, t, 1.7); 7.92-7.85 (2 H, m); 7.73-7.69 (2H, m); 7.61 (1 H, 7, J = 7.8); 7.52-7.46 (2 H, m); 7.43-7.37 (1 H, m);4.81 (1 H, d, J = 4.3); 4.38- 4.31 (1 H, m); 2.78 (1 H, t, J = 7.6);1.72-1.62 (1 H, m); 1.38 (2 H, t, J = 8.7); 1.31 (3 H, d, J = 6.4); 0.94(6 H, d, J = 6.5). E.3.12

Chemical Name: Boronic acid, [(1R)-1-[[(2S,3R)-3-hydroxy-2-[(4-(2-fluorophenyl)benzoyl)amino]-1-oxobutyl]amino]-3- methylbutyl].Analytical Data: ¹H NMR (MeOH-d4): 8.04-7.99 (2 H, m); 7.75-7.69 (2 H,m); 7.59-7.53 (1 H, m); 7.47-7.40 (1 H, m); 7.34- 7.28 (1 H, m);7.28-7.20 (1 H, m); 4.81 (1 H, d, J = 4.2); 4.39-4.30 (1 H, m); 2.79 (1H, 7.63); 1.74-1.62 (1 H, m); 1.42-1.34 (2 H, m); 1.32 (3 H, d, J =6.39); 0.98-0.92 (6 H, m).

Example E.4 Boronic Acid,[(1R)-1-[[(2S,3R)-3-hydroxy-2-[[4-(3-pyridyl)benzoyl]amino]-1-oxobutyl]amino]-3-methylbutyl]

A mixture of 4-(pyridin-3-yl)benzamide,N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]-of Example D.8.3 (155 mg, 0.283 mmol), 2-methylpropylboronic acid (81mg, 0.793 mmol) and 2N aqueous hydrochloric acid (0.3 ml) in aheterogeneous mixture of methanol (3 ml) and hexane (3 ml) was stirredat room temperature for 24 hours. The hexane layer was removed and themethanolic layer was washed with fresh hexane (about 5 ml). Ethylacetate (10 ml) was added to the methanol layer which was thenconcentrated. The residue was taken up with ethyl acetate and themixture was concentrated. This step was repeated (2-3 times) until anamorphous white solid was obtained. The solid was then triturated withdiethyl ether (5 ml) and the surnatant was removed by decantation. Thisstep was repeated. The residue (126 mg) was combined with the product ofa similar preparation (140 mg) and dissolved in ethyl acetate (about 40ml) and a small amount of methanol (2-3 ml). The solution was washedwith a mixture of NaCl saturated solution (7 ml) and 10% NaHCO₃ (2 ml).The layers were separated and the aqueous phase was further washed withethyl acetate (2×20 ml). The combined organic phases were dried oversodium sulfate and concentrated. The residue was taken up with ethylacetate (about 20 ml) and the minimum amount of methanol, and thenconcentrated to small volume (about 5 ml). The resulting white wascollected by filtration and dried under vacuum at 50° C. (160 mg, 65%overall yield).

¹H NMR (MeOH-d4): 8.90 (1H, s); 8.49 (1H, d, J=4.0); 8.20 (1H, d,J=8.1); 8.06 (2H, d, J=8.1); 7.85 (2H, d, J=8.1); 7.58 (1H, t br.,J=6.0); 4.80 (1H, d, J=3.9); 4.40-4.29 (1H, m); 2.78 (1H, t, J=7.5);1.73-1.61 (1H, m); 1.38 (2H, t, J=6.9); 1.31 (3H, d, J=6.3); 0.94 (6H,d, J=6.31).

Further compounds prepared according to the above procedure for ExampleE.4 are reported in Table E-4.

TABLE E-4 Ex # Structure Chemical Name and Analytical Data E.4.1

Chemical Name: Boronic acid, [(1R)-1-[[(2S,3R)-3-hydroxy-2-[(2-pyrazinecarbonyl)amino]-1- oxobutyl]amino]-3-methylbutyl].Analytical Data: ¹H NMR (MeOH-d4): 9.29 (1H, d, J = 1.3); 8.86 (1H, d, J= 1.3); 8.76-8.74 (1H, m); 4.75 (1H, d, J = 3.2); 4.43-4.36 (1H, m);2.77 (1H, t, J = 7.6); 1.72-1.60 (1H, m); 1.40-1.36 (2H, m); 1.27 (3H,d, J = 7.6); 0.92 (6H, d, J = 7.6). E.4.2

Chemical Name: Boronic acid, [(1R)-1-[[(2S,3R)-3-hydroxy-2-[(5-butyl-pyridine-2-carbonyl)amino]-1- oxobutyl]amino]-3-methylbutyl].Analytical Data: ¹H NMR (MeOH-d4): 8.55 (1H, s); 8.04 (1H, d, J = 7.97);7.84 (1H, d, J = 7.96); 4.73 (1H, d, J = 2.15); 4.42-4.33 (1H, m);2.81-2.71 (3H, m); 1.75-1.6 (3H, m); 1.5-1.3 (5H, m); 1.27 (3H, d, J =5.64); 1.02-0.95 (3H, m); 0.94-0.89 (6H, m). E.4.3

Chemical Name: Boronic acid, [(1R)-1-[[(2S,3R)-3-hydroxy-2-[(6-phenyl-pyridine-2-carbonyl)amino]-1- oxobutyl]amino]-3-methylbutyl].Analytical Data: ¹H NMR (MeOH-d4): 8.20 (2H, d, J = 7.52); 8.18-8.12(1H, m); 8.11-8.06 (2H, m); 7.60- 7.43 (3H, m); 4.77 (1H, d, J = 2.66);4.48-4.40 (1H, m); 2.77 (1H, t, J = 7.54); 1.73-1.60 (1H, m); 1.37 (2H,d, J = 7.3); 1.31 (3H, d, J = 6.36); 0.92 (6H, d, J = 6.55).

Example E.5 Boronic Acid,[(1R)-1-[[(2S)-3-(2-pyrazincarbonylamino)-2-[(4-butylbenzoylamino)]-1-oxopropyl]amino]-3-methylbutyl]

2-S-(4-Butylbenzoylamino)-3-(2-pyrazinocarbonylamino)-N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl],from example D.18, (120 mg, 0.19 mmol, 1 eq.), was dissolved in methanol(2 ml), and n-hexane (2 ml). The this solution, Isobutylboronic acid (60mg, 0.57 mmol, 3 eq,) and HCl 4N 1,4-dioxane (0.07 ml, 0.28 mmol, 1.5eq.) have been added. The resulting bifasic mixture was stirred at roomtemperature for 20 h, the n-hexane was removed, the methanolic solutionwas washed with n-hexane (2 ml) and evaporated under reduced pressure.The crude was suspended in diethyl ether/n-hexane/4 ml), stirred at roomtemperature and filtered, to give a white powder. Yield 65%, 69 mg.

Analytical data: M.p. 145°-150° C.

¹H NMR (MeOD-d4): 9.3 (1H, s); 8.85 (1H, s); 8.75 (1H, s); 7.8 (2H, d);7.3 (2H, d); 5.1 (2H, t); 4 (2H, dd); 2.8 (1H, t); 2.75 (2H, t); 1.65(3H, m); 1.4 (4H, m); 1.0 (3H, t) 0.9 (6H, dd).

Further compounds prepared according to the above procedure for ExampleE.5 are reported in Table E-5.

TABLE E-5 Ex # Structure Chemical Name and Analytical Data E.5.1

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-(acetylamino)-2-[(decanoylamino)]-1-oxopropyl]amino]-3- methylbutyl] Analytical Data: ¹HNMR (MeOD-d4): 4.70 (1H, d); 3.50 (2H, m); 2.75 (1H, t); 2.25 (2H, t);2.8 (1H, t); 1.95 (3H, s); 1.65 (3H, m); 1.35 (14H, m); 0.9 (9H, m)E.5.2

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-(propylureido)-2-[(4-butyl)-benzoylamino]-1-oxopropyl]amino]-3- methylbutyl] AnalyticalData: ¹H NMR (MeOD-d4): 7.80 (2H, d); 7.28 (7H, m); 4.45 (1H, br); 3.7(1H, br); 3.1 (2H, t); 2.65 (2H, t); 1.7-1.2 (10H, m); 0.9 (12H, m)E.5.3

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-(methanesulfamido)-2-[(4-butyl)-benzoylamino]-1-oxopropyl]amino]-3-methylbutyl] Analitical Data: ¹H NMR (MeOD-d4):7.80 (2H, d); 7.28 (7H, m); 3.65 (2H, m); 3.0 (3H, s); 2.8 (1H, br);1.65 (3H, m); 1.35 (4H, m); 0.9 (12H, m). M.p. 120°-123° C. E.5.4

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-[2-(1H-pyrazol)ethyl]-2-[(4-butyl)-benzoylamino]-1-oxopropyl]amino]-3-methylbutyl] Analytical Data: ¹H NMR (MeOD-d4): 7.68(2H, d); 7.65 (1H, d); 7.43 (1H, d); 7.27 (1H, m); 7.24 (2H, d); 5.06(1H, t); 4.54 (2H, m); 2.60 (2H, m); 1.5 (3H, m), 1.60-1.3 (4H, m); 0.86(3H, t); 0.80 (6H, d). E.5.5

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-(methanesulfamido)-2-[(4-butyl)-benzoylamino]-1-oxopropyl]amino]-3-methylbutyl] Analytical Data: ¹H NMR (MeOD-d4):7.85 (2H, d); 7.75 (2H, d); 7.35-7.25 (4H, dd); 4.85 (1H, t); 3.9 (2H,dd); 2.8 (1H, t); 2.75 (2H, t); 2.4 (3H, s), 1.65 (3H, m); 1.35 (5H, m);1.05-0.80 (9H, m). E.5.6

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-[(carbobenzyloxyamino]-2-[(4- butylbenzoylamino)]-1-oxopropyl]amino]-3-methylbutyl] Analytical Data: ¹H NMR (MeOD-d4): 7.80 (2H, d); 7.28 (7H,m); 5.2 (2H, dd); 3.6 (2H, d); 2.8 (1H, t); 2.75 (2H, t); 1.65 (3H, m);1.3 (4H, m); 1.0 (9H, m). M.p. 92°- 96° C. E.5.7

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-[(thien-2-ylcarbonyl)amino]-2-[(4-butylbenzoylamino)]-1-oxopropyl]amino]-3-methylbutyl] Analytical Data: ¹H NMR (MeOD-d4): 7.80(2H, d); 7.7 (2H, m); 7.3 (2H, d); 7.2 (1H, t); 4.9 (2H, dd); 3.9 (2H,dd); 2.8 (1H, t); 2.75 (2H, t); 1.65 (3H, m); 1.3 (4H, m); 1.0 (3H, t)0.9 (6H, dd). E.5.8

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-(acetylamino)-2-[4-butyl-benzoylamino)]-1-oxopropyl]amino]-3- methylbutyl] AnalyticalData: ¹H NMR (MeOD-d4): 7.8 (2H, d); 7.3 (2H, d); 4.8 (1H, m); 3.7 (2H,dd); 2.8 (1H, t); 2.75 (2H, t); 2 (3H, s); 1.65 (3H, m); 1.4 (4H, m);1.0-0.9 (3H, t), (6H, dd). M.p. 107°-109° C. E.5.9

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-[(thien-2-ylcarbonyl)amino)]-2-[(decanoylamino)]-1-oxopropyl]amino]-3-methylbutyl] Analytical Data: ¹H NMR (MeOD-d4): t 7.7(2H, d); 7.15 (1H, t); 4.8 (1H, m); 3.7 (2H, dd); 2.8 (1H, t); 2.75 (2H,t); 2.25 (2H, t); 1.65 (3H, m); 1.4 (14H, m); 1.0-0.9 (3H, t). E.5.10

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-(hexanoylamino)-2-[(4-butylbenzoylamino)]-1-oxopropyl]amino]- 3-methylbutyl] AnalyticalData: ¹H NMR (MeOD-d4): 7.8 (2H, d); 7.3 (2H, d); 3.7 (2H, dd); 2.8 (1H,t); 2.75 (2H, t); 2.2 (2H, t); 1.65 (5H, m); 1.4 (9H, m); 1.0-0.9 (12H,t). E.5.11

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-[4-fluoro-benzenesulfonamide]-2-[(4-butylbenzoyl)amino]-1-oxopropyl]amino]-3-methylbutyl] Analytical Data: ¹H NMR (MeOD-d4):7.95 (2H, dd); 7.8 (2H, d); 7.3 (4H, m); 4.8 (1H, m); 3.4 (2H, m); 2.85(1H, t); 2.7 (2H, t); 1.7 (3H, m); 1.4 (4H, m); 1.0-0.9 (9H, t). M.p.130°-132° C. E.5.12

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-[4-fluoro-benzenesulfonamide]-2-[(decanoyl)amino]-1-oxopropyl]amino]-3-methylbutyl] Analytical Data: ¹H NMR (MeOD-d4): 7.95(2H, dd); 7.35 (2H, t); 4.45 (1H, t); 3.0 (2H, m); 3.4 (2H, m); 2.1 (2H,t); 1.65-1.35 (3H, m); 1.25 (14H, m); 0.85 (9H, m). E.5.13

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-(hexanonylamino)-2-[(decanoylamino)]-1-oxopropyl]amino]-3- methylbutyl] Analytical Data:¹H NMR (MeOD-d4): 4.45 (1H, t); 3.3 (2H, m); 2.1 (4H, tt); 1.65-1.35(3H, m); 1.25 (18H, m); 0.85 (12H, m). E.5.14

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-(hexanonylamino)-2-[(cyclopropancarbonylamino)]-1- oxopropyl]amino]-3-methylbutyl]3-methylbutyl]amino]carbonyl]-2- (cyclopropancarbonylamino)ethyl]-Analytical Data: ¹H NMR (MeOD-d4): 7.8 (2H, d); 7.2 (2H, d); 4.6 (1H,br); 3.4 (2H, m); 3.0 (2H, s); 2.7 (2H, m); 1.5 (4H, m); 1.3 (3H, m);1.2 (4H, m); 0.9-0.6 (15H, m). E.5.15

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-[(3,4-dimethoxyphenyl)acetylamino]-2-[(4-butylbenzoylamino)]-1-oxopropyl]amino]-3- methylbutyl] Analytical Data:M.p. 150°-152° C. ¹H NMR (MeOD-d4): 7.7 (2H, d); 7.2 (2H, d); 6.8 (1H,s); 6.75 (2H, m); 4.7 (1H, m); 3.7 (6H, m); 3.54 (2H, s); 3.35 (2H, s);2.66 (3H, t); 1.6 (2H, t); 1.4-1.2 (2H, m); (2H, m); (2H, m); 0.9 (3H,t), 0.8 (6H, d). E.5.16

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-[1-N-methyl-2-pyrrolylcarbonylamino]-2-[(4- butylbenzoyl)amino]-1-oxopropyl]amino]-3-methylbutyl] Analytical Data: ¹H NMR (MeOD-d4): 7.8 (2H, d); 7.3 (2H,d); 6.9 (1H, d); 6.7 (1H, d); 6 (1H, t); 4.8 (1H, t); 3.9 (3H, s); 3.7(2H, m); 2.7 (3H, m); 1.65 (3H, m); 1.35 (4H, m); 0.9-0.6 (9H, m). M.p.130°-135° C. E.5.17

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-[4-sulfamylbenzoylamino]-2-[(4- butylbenzoyl)amino]-1-oxopropyl]amino]-3-methylbutyl] Analytical Data: ¹H NMR (MeOD-d4): 7.95 (4H, dd); 7.8 (2H,d); 7.3 (2H, d); 4.9 (1H, t); 3.7 (2H, d); 2.7 (2H, t); 2.6 (1H, t); 1.6(3H, m); 1.2 (4H, m); 0.95-0.8 (9H, m). M.p. 156°-159° C. E.5.18

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-(nicotinoylamino)-2-[(4-butylbenzoylamino)]-1-oxopropyl]amino]- 3-methylbutyl] AnalyticalData: ¹H NMR (MeOD-d4): 9.1 (1H, s); 8.8 (1H, d); 8.4 (1H, d); 7.8 (2H,d); 7.7 (1H, t); 7.3 (2H, d); 4.9 (1H, t); 3.7 (2H, m); 2.7 (2H, t); 2.6(1H, t); 1.6 (3H, m); 1.4-1.2 (7H, m); 0.95-0.8 (9H, m). E.5.19

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-(3-phenylureido)-2-(4-butylbenzoylamino)-1-oxopropyl]amino]-3- methylbutyl] AnalyticalData: ¹H NMR (MeOD-d4): 8.8 (1H, d); 7.35 (2H, d); 7.25 (2H, d); 7.2(2H, t); 6.9 (1H, t); 4.7 (1H, t); 3.7-3.4 (2H, m); 2.7 (2H, t); 2.6(1H, t); 1.6 (3H, m); 1.4-1.2 (4H, m); 0.95-0.8 (9H, m). E.5.20

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-[(4-methylsulfonyl)benzoylamino]-2-[(4-butylbenzoylamino)]-1-oxopropyl]amino]-3- methylbutyl] Analytical Data:¹H NMR (MeOD-d4): 8.0 (4H, m); 7.8 (2H, d); 7.25 (2H, d); 4.9 (1H, br);3.75 (2H, m); 3.2 (3H, s); 2.7 (2H, t); 2.6 (1H, t); 1.6 (3H, m);1.4-1.2 (4H, m); 0.95-0.8 (9H, m). M.p. 168°-170° C. E.5.21

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-(3-phenylureido)-2-(decanoylamino)-1-oxopropyl]amino]-3- methylbutyl] Analytical Data: ¹HNMR (MeOD-d4): 7.35 (2H, d); 7.28 (2H, dd); 7.0 (2H, t); 3.6 (2H, d);2.75 (1H, t); 2.2 (2H, t); 1.65 (3H, m); 1.3 (14H, m); 0.9 (9H, m)E.5.22

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-(nicotinoylamino)-2-(decanoylamino)-1-oxopropyl]amino]-3- methylbutyl] Analytical Data: ¹HNMR (MeOD-d4): 9.0 (1H, s); 8.8 (1H, d); 8.3 (1H, d); 7.5 (1H, t); 4.9(1H, m); 3.9-3.6 (2H, m); 2.75 (1H, t); 2.2 (2H, t); 1.65 (3H, m); 1.3(14H, m); 1.0-0.9 (9H, m). M.p. 136°-141° C. E.5.23

Chemical Name: Boronic acid, [(1R)-1-[[(2R)-3-(4-methylphenylcarbonyl)-2-(decanoylamino)-1-oxopropyl]amino]-3-methylbutyl] Analytical Data: ¹H NMR (MeOD-d4): 8.85(2H, d); 8.0 (2H, d); 7.3 (4H, m); 5.0 (1H, m); 3.9 (2H, m); 2.75 (3H,m); 1.65 (3H, m); 1.3 (9H, m); 0.9 (9H, m) E.5.24

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-[4-(1H-tetrazolyl)-phenylcarbonylamino]-2-[(4- butylbenzoylamino)]-1-oxopropyl]amino]-3-methylbutyl] Analytical Data: ¹H NMR (MeOD-d4): 8.15 (2H, d); 7.9 (2H,d); 7.8 (2H, d); 7.3 (2H, d); 5.0 (1H, t); 3.9 (2H, m); 2.8 (1H, t); 2.7(2H, t); 1.65 (3H, m); 1.3 (4H, m); 0.9 (9H, m). M.p. >250° C. E.5.25

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-(2-isoxazolylcarbonylamino)-2-[(4-butylbenzoylamino)]-1-oxopropyl]amino]-3- methylbutyl] Analytical Data:¹H NMR (MeOD-d4): 8.4 (1H, s); 7.7 (2H, d); 7.2 (2H, d); 6.9 (1H, s);4.9 (1H, t); 3.8 (2H, m); 2.7 (1H, t); 2.6 (2H, t); 1.5 (3H, m); 1.25(4H, m); 0.8 (9H, m) M.p. 175°-180° C. E.5.26

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-[1-methyl-1H-imidazole-4-sulfamoyl]-2-[(4- butylbenzoyl)amino]-1-oxopropyl]amino]-3-methylbutyl] Analytical Data: ¹H NMR (MeOD-d4): 8.8 (2H, d); 8.7 (2H,s); 7.3 (2H, d); 4.9 (1H, br); 3.8 (3H, s); 3.5 (2H, m); 2.8 (1H, t);2.7 (2H, t); 1.65 (3H, m); 1.35 (4H, m); 0.9 (9H, m), M.p. 120°-123° C.E.5.27

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-[6-morpholin-4-yl-pyridine-3-sulfamoyl]-2-[(4-butylbenzoyl)amino]- 1-oxopropyl]amino]-3-methylbutyl] hydrochloride Analytical Data: ¹H NMR (MeOD-d4): 8.35(1H, s); 8.1 (1H, d); 7.8 (2H, d); 7.3 (3H, m); 4.9 (1H, br); 3.9 (4H,t); 3.8 (4H, t); 3.5 (2H, m); 2.8 (1H, t); 2.7 (2H, t); 1.65 (3H, m);1.35 (4H, m); 0.9 (9H, m). M.p. 182°-184° C. E.5.28

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-(6-morpholinonicotinamide]-2-[(4- butylbenzoyl)amino]-1-oxopropyl]amino]-3-methylbutyl] Analytical Data: ¹H NMR (MeOD-d4): 8.5 (1H, s); 7.9 (1H,d); 7.7 (2H, d); 7.2 (2H, d); 6.7 (1H, d); 4.9 (1H, t); 3.8 (2H, ts);3.7 (4H, d); 3.4 (4H, d); 2.65 (1H, t); 2.6 (2H, t); 1.60 (3H, m); 1.25(4H, m); 0.9 (9H, m). M.p. 178°-180° C. E.5.29

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-(4-(1,3-dimethyl-1H-pyrazole-5-carbonylamino]-2-[(4-butylbenzoyl)amino]-1-oxopropyl]amino]- 3-methylbutyl] hydrochlorideAnalytical Data: ¹H NMR (MeOD-d4): 7.8 (1H, d); 7.3 (2H, d); 6.65 (1H,s); 5.0 (1H, t); 3.9 (2H, m); 2.8 (1H, t); 2.7 (2H, t); 2.3 (3H, s);1.60 (3H, m); 1.35 (4H, m); 0.9 (9H, m). E.5.30

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-[4-fluoro-benzenesulfonamide]-2-[(4- phenoxybenzoyl)amino]-1-oxopropyl]amino]-3-methylbutyl] Analytical Data: ¹H NMR (MeOD-d4): 7.95 (2H, m); 7.9 (2H,d); 7.4 (2H, m); 7.3 (2H, t); 7.25 (1H, t); 7.1 (2H, d); 7.0 (2H, d);3.4 (2H, m); 2.8 (1H, br); 1.7 (1H, m); 1.40 (2H, m); 0.9 (6H, d). M.p.150°-155° C. E.5.31

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-(4-(1,3-dimethyl-1H-pyrazole-5-carbonylamino]-2-[(4-phenoxybenzoyl)amino]-1-oxopropyl]amino]-3-methylbutyl]carbonylamino]ethyl]- Analytical Data: ¹H NMR (MeOD-d4):7.9 (2H, d); 7.45 (2H, t); 7.25 (1H, t); 7.11 (2H, d); 7.05 (2H, d);6.55 (1H, s); 5.0 (1H, t); 4.1 (3H, s); 3.9 (2H, m); 2.8 (1H, t); 2.25(3H, s); 1.6 (1H, m); 1.35 (2H, m); 0.9 (6H, d). M.p. 145°-148° C.E.5.32

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-(4-phenylureido]-2-[(4-phenoxybenzoyl)amino]-1- oxopropyl]amino]- 3-methylbutyl]Analytical Data: ¹H NMR (MeOD-d4): 7.9 (2H, d); 7.40 (2H, t); 7.35 (2H,d); 7.25 (3H, m); 7.10 (2H, d); 7.05 (3H, d); 3.75 (2H, m); 2.8 (1H, t);1.75 (1H, m); 1.4 (2H, m); 0.9 (6H, d). M.p. 155°-158° C. E.5.33

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-(4-phenybenzamide]-2-[(4-butylbenzoyl)amino]-1- oxopropyl]amino]-3-methylbutyl] Analytical Data: ¹H NMR (MeOD-d4): 7.9 (2H, d); 7.8 (2H,d); 7.75 (2H, d); 7.70 (2H, d); 7.45 (2H, t); 7.35 (1H, d); 7.30 (1H,d); 5.0 (1H, t); 3.95 (2H, m); 2.8 (1H, t); 2.7 (2H, t); 1.65 (3H, m);1.4 (2H, m); 1.0 (3H, t) 0.9 (6H, d). M.p. 178°-180° C. E.5.34

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-(4-phenylbenzamide]-2-[(4-phenoxybenzoyl)amino]- 1-oxopropyl]amino]-3-methylbutyl] Analytical Data: ¹H NMR (MeOD-d4): 7.9 (4H, m); 7.80 (2H,d); 7.70 (2H, d); 7.4 (4H, m); 7.20 (1H, t); 7.05 (4H, d); 5.0 (1H, t);3.9 (2H, m); 2.8 (1H, t); 1.6 (1H, m); 1.4 (2H, m); 0.9 (6H, d). M.p.158°-160° C. E.5.35

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-(phenylpropionamide]-2-[(4- butylbenzoyl)amino]-oxopropyl]amino]-3-methylbutyl] Analytical Data: ¹H NMR (MeOD-d4): 7.85 (2H, m); 7.4 (2H,d); 7.5 (1H, d); 7.45 (2H, m); 7.35 (2H, d); 5.0 (1H, t); 3.95 (2H, m);2.8 (1H, t); 2.7 (2H, t); 1.7 (3H, m); 1.4 (4H, m); 1.0 (3H, t) 0.9 (9H,m). M.p. 138°-140° C. E.5.36

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-(4-methylphenylsulfonyl)-ureido]-2-[(4-butylbenzoyl)amino]-1-oxopropyl]amino]- 3-methylbutyl] Analytical Data:¹H NMR (MeOD-d4): 7.85 (2H, d); 7.75 (2H, d); 7.3 (2H, d); 7.25 (2H, d);4.7 (1H, t); 3.65 (2H, m); 2.75 (1H, t); 2.7 (2H, t); 1.7 (3H, m); 1.4(4H, m); 1.0-0.9 (9H, m). M.p. 175°-177° C. E.5.37

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-(4-(2-(4-pyridyl)-1,3-thiazole-4-carbonylamino)]-2-[(4-butylbenzoyl)amino]-1-oxopropyl]amino]- 3-methylbutyl] Analytical Data:¹H NMR (MeOD-d4): 8.7 (2H, d); 8.45 (1H, s); 8.05 (2H, d) 7.8 (2H, d);7.3 (2H, d); 5.05 (1H, t); 4.0 (2H, m); 2.8 (1H, t); 2.7 (2H, t); 1.7(3H, m); 1.4 (4H, m); 0.9 (3H, t); 0.8 (6H, dd). M.p. 155°- 158° C.E.5.38

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-(1-methanesulfonylpiperidine-4-carbonylamino)-2- [(4-butylbenzoylamino)]-1-oxopropyl]amino]-3-methylbutyl] Analytical Data: ¹H NMR (MeOD-d4): 9.9(1H, br); 8.35 (1H, t); 7.8 (2H, d); 7.3 (2H, d); 4.9 (1H, t); 3.7 (4H,m); 2.8 (3H, s); 2.75 (4H, m); 2.3 (1H, m); 1.85-1.6 (7H, m); 1.3 (4H,m) 0.9 (9H, m); M.p. 170°- 173° C. E.5.39

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-[(2-thiophene)sulfonylamino]-2-[(4-butylbenzoylamino)]-1-oxopropyl]amino]-3- methylbutyl] Analytical Data:¹H NMR (MeOD-d4): 7.95 (1H, dd); 7.8 (2H, d); 7.58 (1H, dd); 7.32 (2H,d); 7.18 (1H, dd); 4.8 (1H, m); 3.23 (2H, m); 2.66 (1H, t); 1.3-1.23(8H, m); 0.9 (3H, t), 0.8 (6H, d). E.5.40

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-(4-(1H-1,2,4-triazol-1-yl)benzoylamide)]-2-[(4-butylbenzoyl)amino]-1H-oxopropyl]amino]- 3-methylbutyl] hydrochlorideAnalytical Data: ¹H NMR (MeOD-d4): 9.8 (1H, s); 8.6 (1H, s); 8.08 (2H,d); 8.01 (2H, d); 7.8 (2H, d); 7.3 (2H, d); 5.05 (1H, t); 3.9 (2H, m);2.8 (1H, t); 2.7 (2H, t); 1.6 (3H, m); 1.3 (4H, m); 1.0 (3H, t); 0.9(6H, dd). Mp. 192°-195° C. E.5.41

Chemical Name: Boronic acid, [(1R)-1-[[(2R)-3-(4-methylphenylcarbonyl)-2-(decanoylamino)-1-oxopropyl]amino]-3-methylbutyl] Analytical Data: ¹H NMR (MeOD-d4): 7.85(2H, d); 7.8 (2H, d); 7.35 (4H, m); 5 (1H, m); 4.05 (1H, m); 3.95 (1H,m); 2.75 (2H, t); 1.65 (2H, m); 1.35 (10H, m); 1.0 (3H, t). 0.85 (6H,d). E.5.42

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-(4-phenylureido]-2-(decanoylamino)-1-oxopropyl]amino]- 3-methylbutyl] E.5.43

Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-acetylamino-2-decanoylamino-1-oxopropyl]amino]- 3-methylbutyl]

Example F.1 Decanamide,N-[(1S)-1-[[[(1R)-1-[(4R,5R)-4,5-dicyclohexyl-[1,3,2]dioxaborolan-2-yl]-3-methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl]-

To a suspension of boronic acid,[(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(decanoyl)amino]-1-oxopentyl]amino]-3-methylbutyl]-,(125 mg, 0.26 mmol) obtained as in Example E.2, in a mixture of diethylether (0.5 ml) and dichloromethane (1 ml), a few drops of methanol wereadded until complete dissolution of the solid.(1R,2R)-1,2-dicyclohexyl-1,2-ethanediol (61 mg, 0.26 mmol) was added andthe mixture was stirred at room temperature for 5 hours. The reactionmixture was concentrated to dryness and the residue was purified bycolumn chromatography (silica gel) eluting with a 50:50 ethylacetater:hexane mixture. The product was then triturated with hexane andthe solvent was removed by decantation. The trituration was repeated twofurther times. The product was obtained as a waxy solid (65 mg, 37%yield).

M.p. 75-100° C.

¹H NMR (DMSO-d₆): 8.99 (1H, d, J=2.5 Hz); 8.52 (1H, br); 7.98 (1H, d,J=8.05); 7.88 (2H, br); 3.48 (2H, d, J=5.7); 3.14 (2H, m); 2.55 (1H, m);2.19 (1H, m); 2.10 (2H, m); 1.79 (2H, m); 1.74-1.35 (16H, m); 1.24 (22H,m); 1.12 (5H, m); 0.89 (4H, m); 0.84 (9H, m).

Example F.2 4-Phenylbutanamide,N-[(1S)-1-[[[(1R)-1-[13,15-dioxa-[4-bora-dispiro[5.0.5.3]-pentadec-14-yl]-3-methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]-amino]butyl]-

The title compound was prepared according to the above procedure forExample F.1 using the appropriate boronic acid starting material andbicyclohexyl-1,1′-diol.

Analytical results: ¹H NMR (DMSO-d₆): 8.79 (1H, d, J=2.5 Hz); 8.52 (1H,br); 8.00 (1H, d, J=7.94); 7.85 (2H, br); 7.31-7.23 (2H, m); 7.20-7.14(3H, m); 4.40-4.30 (1H, m); 3.15 (2H, m); 2.55 (3H, m); 2.14 (2H, t,J=7.3 Hz); 1.78 (2H, q, J=7.3 Hz); 1.70-0.97 (27H, m); 0.84 (3H, t,J=6.7 Hz); 0.83 (3H, t, J=6.7 Hz).

Example F.2.1 4-Butylbenzamide,N-[(1S,2R)-1-[[[(1R)-1-[13,15-dioxa-14-bora-dispiro[5.0.5.3]pentadec-14-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]-

The title compound was prepared according to the above procedure forExample F.1 using the appropriate boronic acid starting material andbicyclohexyl-1,1′-diol.

Analytical results: ¹H NMR (DMSO-d₆): 8.98 (1H, s br.); 8.00 (1H, d,J=8.5); 7.81 (2H, d, J=8.2); 7.31 (2H, d, J=8.2); 5.03 (1H, d, J=6.2);4.49 (1H, dd, J=8.5, 5.0); 4.07-3.98 (1H, m); 2.64 (1H, t, J=7.6);2.57-2.50 (1H, m); 1.65-1.21 (21H, m); 1.14-1.00 (9H, m); 0.90 (3H, t,J=7.4); 0.85 (6H, d, 6.5).

Example G.1 10-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-decanoic Acid

Step 1: 2-undec-10-enyl-1,3-dioxo-1,3-dihydroisoindole

To a mixture of 10-undecen-1-ol (4.23 g, 24.8 mmol), phthalimide (3.65g, 24.8 mmol) and triphenylphosphine (6.51 g, 24.8 mmol) in anhydroustetrahydrofuran (30 ml), a solution of DEAD (3.9 ml, 24.8 mmol) inanhydrous tetrahydrofuran (10 ml) was slowly added while keeping thetemperature below 8-10° C. After 2 hours further DEAD (1.0 ml, 6.37mmol) and triphenylphosphine (1.3 g, 4.96 mmol) were added and themixture was stirred at room temperature overnight. The reaction mixturewas concentrated and the residue was triturated with diethyl ether (50ml). The solid was removed by filtration and washed with diethyl ether(2×50 ml). The combined filtrates were concentrated and the residue wastriturated with hexane (50 ml) at 40° C. The resulting solid was removedby filtration and washed with hexane (2×50 ml). The combined filtrateswere concentrated and the residue was purified by column chromatographyeluting with 10:2 hexane:ethyl acetate mixture. The product was obtainedas a low-melting white solid (4.9 g, 66% yield).

M.p. 25-30° C.

¹H NMR (DMSO-d₆) 7.83 (4H, m); 5.76 (1H, m); 4.96 (1H, dq, J=17.2, 1.6Hz); 4.90 (1H, ddt, J=10.2, 2.2, 1.1); 3.54 (2H, t, J=7.1), 1.97 (2H, q,J=6.7); 1.56 (2H, m); 1.35-1.15 (14H, m).

Step 2: 10-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)decanoic Acid

A solution of 2-undec-10-enyl-1,3-dioxo-1,3-dihydroisoindole (2 g, 6.68mmol) of Step 1 and Aliquat® 336 (0.2 g) in a mixture of hexane (20 ml)and acetic acid (6 ml) was added dropwise to a solution of potassiumpermanganate (2.76 g, 20 mmol) in water (28 ml) while cooling at 0° C.The reaction mixture was stirred at room temperature for 7 hours, thenan aqueous solution of sodium bisulfite was added until disappearance ofthe purple colour. The mixture was then extracted with ethyl acetate andthe organic phase was dried over sodium sulfate and concentrated. Theresidue was purified by silica gel column chromatography eluting with2:1 hexane:ethyl acetate mixture. The product was obtained as a whitesolid (1.29 g, 61% yield).

M.p. 58-60° C.

¹H NMR (DMSO-d₆) 11.95 (1H, br); 7.85 (4H, m); 3.55 (2H, t, J=7.2 Hz);2.17 (2H, t, J=7.2 Hz); 1.7-1.4 (4H, m); 1.22 (10H, m).

Example G.2 6-(Benzenesulfonylamino)hexanoic Acid

Benzenesulfonyl chloride (2.5 ml, 19 mmol) was added to a solution of6-aminohexanoic acid (1 g, 7.62 mmol) in 2N NaOH (22 ml) and dioxane (3ml), while stirring at 0° C.-5° C. The mixture was allowed to warm toroom temperature and stirred for 1 hour. The reaction mixture was washedwith ethyl acetate (50 ml), then acidified to pH 2 with 37% hydrochloricacid and extracted with ethyl acetate (2×50 ml). The combined organiclayers were dried over sodium sulfate and concentrated. The residue wastriturated with hexane. The solid was collected by filtration and driedunder vacuum at 50° C. affording 1.1 g of the title compound (55%yield).

M.p. 113-115° C.

¹H NMR (DMSO-d₆): 11.96 (1H, s); 7.79 (2H, m); 7.60 (4H, m); 2.71 (2H,m); 2.13 (2H, t, J=7.14 Hz); 1.38 (4H, m); 1.21 (2H, m).

Example G.3 6-(Ethylsulfonylamino)hexanoic acid

A solution of ethanesulfonyl chloride (3.9 ml, 41.1 mmol) in dioxane (10ml) was added to a solution of 6-aminohexanoic acid (2 g, 15.2 mmol) in1N NaOH (56 ml) and dioxane (10 ml), while stirring at 0° C.-5° C. ThepH of the reaction mixture was adjusted to 8-9 by addition of 25% sodiumhydroxide solution. The mixture was allowed to warm to room temperatureand stirred for 30 minutes. Further 25% NaOH solution was added toadjust the pH to about 11. After 3.5 h 1N hydrochloric acid (15 ml) andethyl acetate (60 ml) were added. The organic layer was dried oversodium sulfate and concentrated. The residue was triturated with amixture of diethyl ether (5 ml) and hexane (15 ml). The solid wascollected by filtration and dried affording 1.3 g of the title compound(40% yield).

¹H NMR (DMSO-d₆): 11.9 (1H, s); 6.97 (1H, t, J=5.7 Hz); 2.97 (2H, q,J=7.1); 2.88 (2H, q, J=6.6); 2.2 (2H, t, J=7.3); 1.47 (4H, m); 1.29 (2H,m); 1.18 (3H, t, J=7.3).

Example G.4 8-(Ethylsulfonylamino)octanoic Acid

A solution of ethanesulfonyl chloride (1.5 ml, 15.7 mmol) in dioxane (5ml) was added to a solution of 8-aminooctanoic acid (1 g, 6.28 mmol) in1N NaOH (22 ml) and dioxane (5 ml), while stirring at 0° C.-5° C. Themixture was allowed to warm to room temperature and stirred for 3.5minutes. During this period, at 1 hour intervals, the pH was adjusted to7-8 by addition of 25% NaOH solution. The reaction mixture was washedwith diethyl ether (30 ml). The pH was adjusted to 1-2 by addition of 1NHCl and the mixture was extracted with ethyl acetate (70 ml). Theorganic layer was dried over sodium sulfate and concentrated. Theresidue was triturated with a mixture of diethyl ether. The solid wascollected by filtration and dried under vacuum affording 600 mg of thetitle compound (38% yield).

¹H NMR (DMSO-d₆): 11.9 (1H, s); 6.96 (1H, t, J=6 Hz); 2.96 (2H, q,J=7.1); 2.88 (2H, q, J=6.6); 2.2 (2H, t, J=7.3); 1.45 (4H, m); 1.26 (6H,m); 1.18 (3H, t, J=7.3).

Example G.5 3-Amino-2-S-[(1,1-dimethylethoxycarbonyl)amino]-propionicAcid, Benzyl Ester

Step 1: N-tert-butoxycarbonyl-L-asparagine [Commercially Available]

L-asparagine (15 g, 0.113 mol, 1 eq.) and sodium carbonate (12 g, 0.113mol) were dissolved in water (225 ml) and 1,4-dioxane (225 ml) at r.t.To this solution, di-tert-butyl-dicarbonate (30 g, 0.137 mol, 1.2 eq.)was added and the mixture was stirred overnight. The solvent wasevaporated under reduced pressure till 1,4-dioxane was distilled and thepH adjusted to 2 with HCl 37% to give a white solid that was filtered,washed with water and dried. Yield 91%. 24 g.

Analytical data: m.p. 175° C.-180° C. (lit. 175° C.).

¹H NMR (DMSO-d₆) 12.5 (1H, br); 7.31 (1H, br); 6.91 (1H, br); 6.87 (1H,d, J=8.4 Hz); 4.23 (1H, q, J=7.7 Hz); 2.56-2.36 (2H, m); 1.38 (9H, s).

Step 2: N-[(1,1-Dimethylethoxycarbonyl)amino]-L-asparagine, Benzyl Ester

The compound was prepared according to Bioorg. Med. Chem., 6 (1998)1185-1208. N-[(1,1-dimethylethoxycarbonyl)amino]-L-asparagine (20.7 g,89.1 mmol, 1 eq.), of Step 1, was dissolved in methanol (500 ml) andcesium carbonate (15.97 g, 49 mmol, 0.55 eq.) was added. The solvent wasevaporated to give a white solid that was dissolved inN,N-dimethylformamide (200 ml). To the suspension, benzyl bromide (11.6ml, 98 mmol, 1.1 eq.) was added dropwise and the mixture was stirredovernight. The solvent was reduced under reduced pressure, water (300ml) was added and the mixture extracted with ethyl acetate (200 ml),washed with brine (50 ml) and the solvent removed under reduced pressureto give a crude that was suspended in n-hexane (160 ml), filtered anddried under vacuum to give 14.68 g of white solid. Yield 51%.

Analytical data: m.p. 113°-115° C.

¹H NMR (DMSO-d₆) 7.35 (6H, m); 7.13 (1H, d, J=7.9 Hz); 6.94 (1H, br s);5.10 (2H, s); 4.39 (1H, q, J=7.4 Hz); 2.6-2.4 (2H, m); 2.03 (2H, t,J=7.3); 1.37 (9H, s).

Step 3: 3-Amino-2-S-[(1,1-dimethylethoxycarbonyl)amino]-propionic Acid,Benzyl Ester

N-[(1,1-dimethylethoxycarbonyl)amino]-L-asparagine, benzyl ester, (2 g,6.3 mmol, 1 eq.), of Step 2, was dissolved in acetonitrile (80 ml) andwater (80 ml). The solution was cooled to 0°-5° C. and iodobenzenediacetate (3 g, 9.3 mmol, 1.5 eq.) was added portionwise. The mixturewas stirred at 0° C. for 30′, then at r.t. for 4 h. The organic solventwas removed under vacuum, diethyl ether and HCl 1N were added. Theaqueous layer was separated and extracted with dichloromethane (100 ml)and sodium bicarbonate (3.5 g). The organic solvent was dried oversodium sulphate anhydrous, evaporated under reduced pressure to give0.65 g of colourless oil. Yield 36%

Analytical data:

¹H NMR (DMSO-d₆) 7.45-7.20 (7H, m); 7.20 (1H, d, J=7.7 Hz); 5.13 (2H, ABq, J=12.8); 4.01 (1H, m); 2.80 (2H, m); 1.38 (9H, s).

Example G.6(2S)-2-[(1,1-Dimethylethoxycarbonyl)amino]-3-[(4-methylbenzoyl)amino]propanoicAcid

Step 1:2-S-[(1,1-Dimethylethoxycarbonyl)amino]-3-(4-methylbenzoylamino)propionicAcid, Benzyl Ester

3-Amino-2-S-[(1,1-dimethylethoxycarbonyl)amino]-propionic acid, benzylester, (690 mg, 2.34 mmol, 1 eq.), of Example G.5, was dissolved in DMFdry (20 ml) and TBTU (900 mg, 2.98 mmol, 1.2 eq.) was added. The mixturewas stirred at r.t. for 10′, cooled to 0°-5° C. with ice bath and NMM(0.51 ml, 4.68 mmol, 2 eq.) and 4-methyl benzoic acid (380 mg, 2.81mmol, 1.2 eq.) were added. The mixture was stirred at r.t. for 3 h,poured in water (100 ml) and extracted with ethyl acetate (100 ml). Theorganic layer was washed with a solution of citric acid 2% (50 ml),sodium bicarbonate 2% (50 ml), NaCl 2% (50 ml), dried over sodiumsulphate anhydrous and evaporated at reduced pressure to give 1 g ofoil. Yield quantitative.

Analytical data:

¹H NMR (DMSO-d₆) 8.46 (1H, br t, J=5.7 Hz); 7.70 (2H, d, J=8.0);7.35-7.2 (8H, m); 5.07 (2H, s); 4.29 (1H, m); 3.67 (1H, m); 3.58 (1H,m); 2.36 (3H, s); 1.37 (9H, s).

Step 2:(2S)-2-[(1,1-Dimethylethoxycarbonyl)amino]-3-(4-methylbenzoylamino)propionicAcid

2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(4-methylbenzoylamino)-propionicacid, benzyl ester, (930 mg, 2.25 mmol), of Step 1, was dissolved inmethanol (25 ml) and Pd/C 10% (90 mg) was added. The mixture washydrogenated at atmospheric pressure for 1 h. Pd/C was filtered and thesolution was evaporated under reduced pressure to give 650 mg of whitefoam. Yield 86%. Analytical data:

¹H NMR (DMSO-d₆): 12.5 (1H, br); 8.40 (1H, t, J=5.7 Hz); 7.71 (2H, d,J=8.05 Hz), 7.27 (2H, d, J=8.05 Hz); 7.09 (1H, d, J=7.9), 4.17 (1H, m);3.57 (2H, m); 2.35 (3H, s); 1.37 (9H, m).

Example G.72-S-[(1,1-Dimethylethoxycarbonyl)amino]-3-(hexanoylamino)propionic Acid

Step 1:2-S-[(1,1-Dimethylethoxycarbonyl)amino]-3-(hexanoylamino)propionic Acid,Benzyl Ester

Hexanoic acid (450 mg, 3.87 mmol, 1.2 eq.) was dissolved in DMF dry (15ml) and TBTU (1.24 g, 3.87 mmol, 1.2 eq.) was added, the mixture wasstirred at r.t. for 20′, then was cooled to 0°-5° C. with ice bath.3-amino-2-S-[(1,1-dimethylethoxycarbonyl)amino]propionic acid, benzylester, (950 mg, 3.22 mmol, 1 eq.), of Example G.5, and NMM (1.06 ml,9.61 mmol, 2.5 eq.) were added. The mixture was stirred at r.t.overnight, poured in water (150 ml) and extracted with ethyl acetate(100 ml). The organic layer was washed with a solution of citric acid 2%(50 ml), sodium bicarbonate 2% (50 ml), NaCl 2% (50 ml), dried oversodium sulphate anhydrous and evaporated at reduced pressure to give acrude that was purified by silica gel column chromatography (eluent:n-hexane/ethyl acetate 2/1, R.f=0.52) 0.5 g of colourless oil.

Yield 40%.

Analytical data:

¹H NMR (DMSO-d₆).

δ_(H): 7.87 (1H, br t, J=6.2 Hz); 7.35 (5H, m); 7.14 (1H, d, J=8.2);5.07 (2H, s); 4.14 (1H, m); 3.37 (2H, m); 2.00 (2H, t, J=7.1); 1.43 (2H,m); 1.36 (9H, s); 1.3-1.1 (4H, m); 0.83 (3H, t, J=7.1 Hz)

Step 2:2-S-[(1,1-Dimethylethoxycarbonyl)amino]-3-(hexanoylamino)propionic Acid

2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(hexanoylamino)propionic acid,benzyl ester (500 mg, 1.27 mmol), of Step 1, was dissolved in methanol(15 ml) and Pd/C 10% (50 mg) was added. The mixture was hydrogenated atatmospheric pressure for 1 h. Pd/C was filtered and the solution wasevaporated under reduced pressure to give 300 mg of white solid. Yield78%.

Analytical data: m.p. 123°-125° C.

¹H NMR (DMSO-d₆).

δ_(H): 12.6 (1H, br); 7.84 (1H, br t); 6.87 (1H, d, J=7.5 Hz); 4.00 (1H,m); 3.32 (2H, m); 2.04 (2H, t, J=7.5); 1.47 (2H, m); 1.38 (9H, s);1.3-1.1 (4H, m); 0.85 (3H, t, J=7.1 Hz)

Example G.82-S-tert-Butoxycarbonylamino-3-(4-fluorosulfonylamino)propionic Acid

Step 1:2-S-[(1,1-Dimethylethoxycarbonyl)amino]-3-(4-fluorosulfonylamino)propionicAcid, Benzyl Ester

3-Amino-2-S-[(1,1-dimethylethoxycarbonyl)amino]propionic acid, benzylester (1.25 g, 4.24 mmol, 1 eq.), of Example G.5, was dissolved indichloromethane dry (20 ml) and the solution was cooled to 0°-5° C.,under nitrogen. TEA (0.65 ml, 4.67 mmol, 1.1 eq.) and4-fluoro-sulfonylchloride (0.9 g, 4.67 mmol, 1.1 eq.) in dichloromethanedry (10 ml) were added. The mixture was stirred at r.t. for 1 h,evaporated under reduced pressure and diethyl ether (25 ml) was addedand a white solid was obtained that was filtered and dried under vacuumto give 1.89 g of product.

Yield 99%.

Analytical data: m.p. 105°-107° C. TLC silica gel (eluent:n-hexane/ethyl acetate 1/1, R.f=0.55).

¹H NMR (DMSO-d₆).

δ_(H): 7.91 (1H, t, J=6.2 Hz); 7.85 (2H, dd, J=5.3, 8.8); 7.43 (2H, t,J=8.8); 7.35 (5H, m); 7.15 (1H, d, J=8.2); 5.09 (2H, s); 4.14 (1H, m);3.10 (2H, m); 1.36 (9H, s).

Step 2:2-S-[(1,1-Dimethylethoxycarbonyl)amino]-3-(4-fluorosulfonylamino)propionicAcid

2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(4-fluorosulfonylamino)propionicacid, benzyl ester (1.8 g, 3.98 mmol), of Step 1, was dissolved inmethanol (30 ml) and Pd/C 10% (180 mg) was added. The mixture washydrogenated at atmospheric pressure for 1 h. Pd/C was filtered and thesolution was evaporated under reduced pressure to give 1.39 g ofcolourless oil. Yield 97%.

Analytical data:

¹H NMR (DMSO-d₆).

δ_(H): 12.7 (1H, br); 7.83 (2H, dd, J=5.3, 8.8); 7.78 (1H, br t, J=5.5);7.42 (2H, t, J=8.8); 6.87 (1H, d, J=8.6); 3.99 (1H, m); 3.03 (2H, m);1.36 (9H, s).

Example G.92-S-[(1,1-Dimethylethoxycarbonyl)amino]-3-(3,4-dimethoxyphenylacetamido)-propionicAcid

Step 1:2-S-[(1,1-Dimethylethoxycarbonyl)amino]-3-(3,4-dimethoxyphenylacetamido)-propionicAcid, Benzyl Ester

3,4-Dimethoxy-phenylacetic acid (720 mg, 3.66 mmol, 1.2 eq.) wasdissolved in DMF dry (20 ml) and TBTU (1.17 g, 3.66 mmol, 1.2 eq.) wasadded, the mixture was stirred at r.t. for 20′, then was cooled to 0°-5°C. with ice bath. 3-amino-2-S-tert-butoxycarbonylamino-propionic acid,benzyl ester (0.9 g, 3.05 mmol, 1 eq.), of Example G.5, and NMM (1.0 ml,9.15 mmol, 2.5 eq.) were added. The mixture was stirred at 0° C. for 2h, then poured in water (200 ml) and extracted with ethyl acetate (100ml). The organic layer was washed with the following solutions: citricacid 2% (20 ml), sodium bicarbonate 2% (20 ml), NaCl 2% (20 ml), driedover sodium sulphate anhydrous and evaporated at reduced pressure togive a crude that was purified by silica gel chromatography (eluent:n-hexane/ethyl acetate 1/1, R.f=0.57) to give 1 g of colourless oil.Yield 69%.

Analytical data: ¹H NMR (DMSO-d₆). δ_(H): 8.02 (1H, t, J=5.7 Hz); 7.34(5H, m); 7.17 (1H, d, J=7.7); 6.82 (2H, m); 6.71 (1H, dd, J=1.5, 8.2);5.03 (2H, s); 4.14 (1H, m); 3.71 (3H, s); 3.69 (3H, s); 3.39 (2H, m);1.36 (9H, s).

Step 2:2-S-[(1,1-Dimethylethoxycarbonyl)amino]-3-(3,4-dimethoxyphenylacetamido)-propionicAcid

2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(3,4-dimethoxyphenylacetamido)-propionicacid, benzyl ester (1 g, 2.1 mmol), of Step 1, was dissolved in methanol(30 ml) and Pd/C 10% (10 mg) was added. The mixture was hydrogenated atatmospheric pressure for 1 h. Pd/C was filtered and the solution wasevaporated under reduced pressure to give 0.73 g of white foam. Yield91%.

Analytical data: ¹H NMR (DMSO-d₆). δ_(H): 12.7 (1H, br); 8.06 (1H, t,J=5.9 Hz); 7.00 (1H, d, J=8.05); 6.91 (2H, m); 6.80 (1H, dd, J=1.5,8.4); 4.08 (1H, m); 3.80 (3H, s); 3.78 (3H, s); 3.5-3.3 (2H, m); 1.36(9H, s).

Example G.102-[(1,1-Dimethylethoxycarbonyl)amino]-3-(3-phenylureido)propionic Acid

Step 1:2-[(1,1-Dimethylethoxycarbonyl)amino]-3-(3-phenylureido)propionic Acid,Benzyl Ester

3-Amino-2-S-[(1,1-dimethylethoxycarbonyl)amino]propionic acid, benzylester (1.14 g, 3.87 mmol, 1 eq.), of Example G.5, was dissolved indichloromethane (20 ml) at r.t., The solution was cooled to 0°-5° C. andphenyl isocyanate (0.42 ml, 3.87 mmol, 1 eq.) in dichlorometane (5 ml)was added dropwise. The solution was stirred at r.t. for 1 h, evaporatedunder reduced pressure and purified by silica gel chromatography (eluentn-hexane/ethyl acetate 1/1) to give 0.71 g of glassy solid that wassuspended in diethyl ether to give a white solid. Yield 44%. Analyticaldata: TLC silica gel (eluent n-hexane/ethyl acetate 1/1 R.f.=0.44), m.p.48°-50° C.

¹H NMR (DMSO-d₆). δ_(H): 8.68 (1H, s); 7.4-7.27 (8H, m); 7.22 (2H, t,J=8.2 Hz); 6.90 (1H, t, J=7.3); 6.26 (1H, t, J=5.7); 5.11 (2H, s); 4.12(1H, m); 3.58 (1H, m); 3.28 (1H, m); 1.38 (9H, s).

Step 2:2-[(1,1-Dimethylethoxycarbonyl)amino]-3-(3-phenylureido)propionic Acid

2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(3-phenylureido)propionicacid, benzyl ester (0.7 g, 1.7 mmol), of Step 1, was dissolved inmethanol (25 ml) and Pd/C 10% (70 mg) was added. The mixture washydrogenated at atmospheric pressure for 1 h. Pd/C was filtered and thesolution was evaporated under reduced pressure to give 0.47 g of desiredproduct. Yield 87%.

Analytical data: ¹H NMR (DMSO-d₆). δ_(H): 12.6 (1H, br); 8.66 (1H, s);7.37 (2H, d, J=8.1 Hz); 7.21 (2H, t, J=7.50); 7.08 (1H, d, J=7.9); 6.89(1H, t, J=7.3); 6.21 (1H, t, J=5.9); 3.98 (1H, m); 3.54 (1H, m); 3.22(1H, m); 1.38 (9H, s).

Example G.11 Synthesis of Further Compounds

The following compounds can be prepared starting from3-amino-2-S-[(1,1-dimethylethoxycarbonyl)amino]propionic acid, benzylester of Example G.5, with the methods described in Step 1 and Step 2 ofExamples G.6-G.10.

G.11.1 2-[(1,1- dimethylethoxy- carbonyl)amino]-3- (acetamido)propionicacid.

G.11.2 2-[(1,1- dimethylethoxy- carbonyl)amino]- 3-(9-fluorenyl-methyloxy- carbamoyl)) propionic acid.

G.11.3 2-[(1,1- dimethylethoxy- carbonyl)amino]- 3-(3-pentylureido)propionic acid.

G.11.4 2-[(1,1- dimethylethoxy- carbonyl)amino]-3- (methanesolfonamido)propionic acid.

G.11.5 2-[(1,1- dimethylethoxy- carbonyl)amino]-3- [(ethoxycarbonyl-succinyl]-amide) ethyl]- propionic acid.

Example G.122-[(1,1-Dimethylethoxycarbonyl)amino]-3-(3-benzyloxycarbonylamino)propionicAcid

Step 1: N²-(tert-Butoxycarbonyl)-L-2,3-diaminopropionic Acid

N-tert-butoxycarbonyl-L-asparagine, from step 1 of Example G.5 orcommercially available, (8 g, 0.034 mol, 1 eq.) was suspended in ethylacetate (72 ml), acetonitrile (72 ml) and water (36 ml), andIodobenzenediacetate (13.3 g, 0.041 mol, 1.2 eq.) was added at 5° C. Themixture was stirred at 10°-25° C. for 3-4 h, then a white solid cameoff. The solid was filtered, washed with diethyl ether and dried undervacuum to give a white powder. Yield 57%. 4 g.

Analytical data: m.p. 210° C.-211° C. Silica gel(dichloromethane/methanol/acetic acid 5/3/1) Rf 0.5. ¹H NMR (DMSO-d₆)4.15 (1H, t); 3.15 (2H, m); 1.45 (9H, s);

Step 2:2-[(1,1-Dimethylethoxycarbonyl)amino]-3-(3-benzyloxycarbonylamino)propionicAcid

N²-(tert-Butoxycarbonyl)-L-2,3-diaminopropionic acid, from step 1, (3.8g, 0.018 mol, 1 eq.) was dissolved in aqueous sodium carbonate 10% (2.2eq.) at 25° C. and 1,4-dioxane (38 ml). To this solution,benzylchloroformate (3 ml, 0.020 mol, 1.1 eq.) was added dropwise andthe solution was stirred at 25° C. for 3 h. At the end of the reaction,the mixture was poured in water (100 ml) and washed with diethyl ether(100 ml). To the aqueous solution, HCl 37% (6 ml) was added till pH 2and the obtained mixture was extracted with Ethyl Acetate (100 ml). Theorganic layer was separated, washed with brine and dried over sodiumsulfate anhydrous. The solvent was removed under reduced pressure togive a colourless oil that under vacuum gave a white foam.

Yield 93%, 5.9 g.

Analytical data: silica gel (dichloromethane/methanol/acetic acid 5/3/1)Rf 1.

¹H NMR (DMSO-d₆) 12.6 (1H br s); 7.35 (5H m); 6.94 (1H, d); 5 (2H, s);4.1 (2H, m); 1.4 (9H, s).

Example G.13 2-(tert-Butoxycarbonilamino)-3-pyrazol-1-yl-propionic Acid

The intermediate was prepared according to the procedure described inVederas, J. Am. Chem. Soc., 1985, 107, 7105-7109.

Example G.14 1-Methanesulfonyl-piperidine 4-carboxylic Acid

Step 1: 1-[(1,1-Dimethylethoxycarbonyl)amino]-piperidine-4-carboxylicAcid

Piperidine-4-carboxylic acid (5 g, 38.7 mmol, 1 eq.) was dissolved insodium carbonate solution (4.5 g, 42.6 μmol, 2.2 eq.), 70 ml, and1,4-dioxane (30 ml). A solution of di-tert-butyldicarbonate (9.3 g,42.61 mmol, 1.1 eq.) in 1,4-dioxane (40 ml) was added dropwise and theresulting mixture was stirred overnight at room temperature. The organicsolvent was removed under reduced pressure and the resulting solutionwas acidified with HCl 37% till pH 2. The obtained suspension wasfiltered, the white solid washed with diethyl ether (5 ml). The motherliquor has been extracted with ethyl acetate (120 ml) and the previoussolid was added. The organic solution was dried over anhydrous sodiumsulfate, evaporated under reduced pressure to give a white solid thatwas dried at 80° C. under vacuum to give the title compound. Yield 93%,8.2 g.

Analytical data: m.p. 133°-135° C.

¹H NMR (DMSO-d₆) 12.3 (1H br s); 3.85 (2H, d); 2.8 (2H, br); 2.35 (1H,t); 1.8 (2H, d); 1.4 (11H, m).

Step 2: 1-[(1,1-Dimethylethoxycarbonyl)amino]-piperidine-4-carboxylicAcid Benzyl Ester

1-[(1,1-Dimethylethoxycarbonyl)amino]-piperidine-4-carboxylic acid (6 g,26.16 mmol, 1 eq.), from step 1, was dissolved in methanol (150 ml) andcesium carbonate (4.26 g, 13.08 mmol, 0.5 eq.) was added. The mixturewas stirred at room temperature for 2 h, the solvent was removed underreduced pressure. The crude was dissolved in DMF (100 ml) andbenzylbromide (5.37 g, 31.39 mmol, 1.2 eq.) was added dropwise. Themixture was stirred overnight at room temperature and poured in water(300 ml), extracted with Ethyl Acetate (900 ml) The organic layer wasdried over anhydrous sodium sulfate and evaporated under reducedpressure to give a white solid.

Yield 95%, 7 g.

Analytical data:

¹H NMR (DMSO-d₆) 7.3 (5H m); 5.1 (2H, s); 3.85 (2H, d); 2.8 (2H, br);2.65 (1H, t); 1.8 (2H, d); 1.4 (11H, m).

Step 3: Piperidine-4-carboxylic Acid Benzyl Ester, Hydrochloride Salt

1-[(1,1-Dimethylethoxycarbonyl)amino]-piperidine-4-carboxylic acidbenzyl ester (7 g, 21.0 mmol), from step 2, was dissolved in 1,4-dioxane(20 ml). To this solution, HCl 4N in 1,4-dioxane (7.8 ml, 300 ml, 12eq.) was added and the resulting solution was stirred overnight at roomtemperature. The solid was filtered, suspended in n-hexane (50 ml), andfiltered to give a white solid. Yield 54%, 2.5 g.

Analytical data:

¹H NMR (DMSO-d₆) 8.9 (2H, br); 7.35 (5H, m); 5.1 (2H, s); 3.25 (2H, d);2.9 (2H, t); 2.75 (1H, m); 2.0 (2H, m); 1.8 (2H, m).

Step 4: 1-Methanesulfonyl-piperidine-4-carboxylic Acid Benzyl Ester

Piperidine-4-carboxylic acid benzyl ester, hydrochloride salt (1 g, 3.9mmol, 1 e.) from step 3, was dissolved in DMF (15 ml), Triethylamine(0.55 ml, 4 mmol, 1 eq.) and methanesulfonylchloride were added. Themixture was stirred for 1 h at room temperature, then was poured inwater (20 ml). The aqueous solution was extracted with Ethyl Acetate (90ml) and the organic layer was dried over anhydrous sodium sulfate,evaporated under reduced pressure to give a colourless oil. Yield 78%,0.9 g.

Analytical data:

¹H NMR (DMSO-d₆) 7.35 (5H, m); 5.1 (2H, s); 3.5 (2H, d); 2.8 (5H, m);2.6 (1H, m); 2.0 (2H, m); 1.6 (2H, m).

Step 5: 1-Methanesulfonyl-piperidine 4-carboxylic Acid

1-Methanesulfonyl-piperidine-4-carboxylic acid benzyl ester (0.8 g, 26.7mmol) from step 4, was dissolved in ethyl acetate (100 ml) and methanol(10 ml), Pd/C 10% (80 mg) was added and the resulting mixture washydrogenated at 1 bar. The catalyst was filtered over celite, thesolvent was removed under reduced pressure to give a white solid. Yield73%, 0.4 g

Analytical data:

¹H NMR (DMSO-d₆) 12.4 (1H, br); 3.6 (2H, d); 2.9 (4H, m); 2.4 (1H, m);2.0 (2H, m); 1.6 (2H, m).

Example G.15 (4-Methylphenyl)-ureido-sulfonylchloride

This compound was prepared according to J. Med. Chem. 1996, 39,1243-1252. Briefly, a solution of chlorosulfonylisocyanate (1.62 g, 11.5mmol, 1 eq.) was diluted in dry diethylether and the resulting solutionwas cooled at −50° C.<T<−40° C. To this solution, p-toluidine (1.23 g,11.5 mmol, 1 eq.) was added. The solution was stirred at −35° C. for 10′and a suspension was obtained. The solid was filtered and washed withdiethyl ether. Yield 80%, 2.3 g.

Analytical data: m.p. 127°-129° C.

¹H NMR (DMSO-d₆) 9.9 (1H, s); 7.3 (2H, d); 7.1 (2H, d); 2.25 (3H, s);

Example G.16 Isoxazole-5-carboxylic Acid

The desired carboxylic acid was prepared according to the procedure byWolfang et al., Synthesis, 1986, 69-70.

Utility

Compound Activity

The present compounds can inhibit proteasome activity. Table F-1 belowprovides data related to several Example compounds of the invention withrespect to, for example, ability to inhibit proteasome activity.

Methods and Compositions

Compounds of the present invention can inhibit the activity ofproteasome leading to the inhibition or blocking of a variety ofintracellular functions with which the proteasome is directly orindirectly associated. For example, proteasome inhibitors can modulate,such as induce, apoptosis in a cell. In some embodiments, the compoundsherein can kill tumor cells by induction of apoptosis. Thus, the presentcompounds can be used to treat cancer, tumors or other proliferativedisorders.

In further embodiments, inhibition of proteasome function by compoundsof the invention can inhibit the activation or processing oftranscription factor NF-κB. This protein plays a role in the regulationof genes involved in the immune and inflammatory responses as well as incell viability Inhibition of proteasome function can also inhibit theubiquitination/proteolysis pathway. This pathway catalyzes, inter alia,selective degradation of highly abnormal proteins and short-livedregulatory proteins. In some embodiments, compounds of the invention canprevent the degradation of p53 which is typically degraded by theubiquitin-dependent pathway. The ubiquitination/proteolysis pathway alsois involved in the processing of internalized cellular or viral antigensinto antigenic peptides that bind to MHC-I molecules. Thus, thecompounds of the invention can be used to reduce the activity of thecytosolic ATP-ubiquitin-dependent proteolytic system in a number of celltypes.

Accordingly, the usefulness of such compounds can include therapeutics,such as the treatment of various diseases or disorders associated withproteasome. The methods include administering a therapeuticallyeffective amount of a compound of the invention, or composition thereof,to a mammal, such as a human having a disease or disorder associatedwith proteasome. The phrase “therapeutically effective amount” refers toan amount sufficient to prevent, alleviate, or ameliorate anyphenomenon, such as a cause or symptom, known in the art to beassociated with the disease or disorder.

Treatable diseases or disorders (abnormal physical conditions) can beassociated with either normal or abnormal activities of proteasome, suchas the regulation of apoptosis. Numerous diseases or disorders that areassociated with proteasome, or that are desirably treated by inductionof apoptosis, are known and include, for example, various cancers andtumors including those associated with skin, prostate, colorectal,pancreas, kidney, ovary, mammary, liver, tongue, lung, and smooth muscletissues. Preferred tumors that can be treated with proteasome inhibitorsinclude, but are not limited to hematological tumors, such as, forexample, leukemias, lymphomas, non-Hodgkin lymphoma, myeloma, multiplemyeloma, as well as solid tumors such as, for example, colorectal,mammary, prostate, lung, and pancreas tumors. In order to elicittherapeutic effects, the proteasome inhibitors can be administered topatients as single agents or in combination with one or more antitumoror anticancer agent and/or radiotherapy. Examples of other anti-tumor oranti-cancer agents which can be advantageously administeredconcomitantly with a proteasome inhibitor include but are not limitedto, adriamycin, daunomycin, methotrexate, vincristin, 6-mercaptopurine,cytosine arabinoside, cyclophosphamide, 5-FU, hexamethylmelamine,carboplatin, cisplatin, idarubycin, paclitaxel, docetaxel, topotecan,irinotecam, gemcitabine, L-PAM, BCNU and VP-16. Methods for determiningapoptosis in vitro are well known in the art and kits are availablecommercially. See for example the Apo-ONE™ Homogeneous Caspase-3/7 Assayfrom Promega Corporation, Madison Wis., USA (Technical Bulletin No. 295,revised 2/02, Promega Corporation).

Further diseases or disorders associated with the proteasome includeaccelerated or enhanced proteolysis that occurs in atrophying muscles,such as is often associated with activation of a nonlysomalATP-requiring process involving ubiquitin. Accelerated or enhancedproteolysis can be the result of any of numerous causes includingsepsis, burns, trauma, cancer, infection, neurodegenerative diseasessuch as muscular dystrophy, acidosis, or spinal/nerve injuries,corticosteroid use, fever, stress, and starvation. Compounds of theinvention can be tested for inhibition of muscle wastage by any variousprocedures known in the art such as by measuring urinary excretion ofmodified amino acid 3-methylhistidine (see, e.g., Young, et al.,Federation Proc., 1978, 37, 229).

Compounds of the present invention can be further used to treat orprevent diseases or disorders associated with activity of NF-κBincluding for example, human immunodeficiency virus (HIV) infection andinflammatory disorders resulting from, for example, transplantationrejection, arthritis, infection, inflammatory bowel disease, asthma,osteoporosis, osteoarthritis, psoriasis, restenosis, and autoimmunediseases. Accordingly, a process that prevents activation of NF-κB inpatients suffering from such a disease would be therapeuticallybeneficial. Inhibition of the NF-κB activity can be measured by using aDNA binding assay such a described in Palombella, et al., Cell, 1994,78, 773.

Those of ordinary skill in the art can readily identify individuals whoare prone to or suspected of suffering from such diseases or disordersusing standard diagnostic techniques.

Example A

Assay for Chymotrypsin-like Activity of 20S Human Erythrocyte Proteasome(HEP)

Proteasome chymotrypsin-like activity of compounds of the invention wasassayed according to the following procedure.

In 96-well microtiter plates, 20S Human Erythrocyte Proteasome (HEP),purchased from Immatics Biotechnologies Inc., Tübingen, Germany wasplated at 0.2 μg/mL (about 0.6 nM catalytic sites) in 0.04% SDS 20 mMTris buffer. A fluorimetric substrate Suc-LLVY-AMC(succinyl-Leu-Leu-Val-Tyr-7-amido-4-methylcoumarin), purchased fromSigma Inc., St. Louis, Mo., USA was added to a final concentration of100 μM from a stock solution of 10 mM in dimethylsulfoxide. Reactionvolumes were 100 μl per well. After incubation for various periods oftime at 37° C., the concentration of free AMC (aminomethylcoumarin) wasdetermined on a Perkin Elmer HTS 7000 Plus microplate reader, excitation370 nM and emission 465 nM. Proteasome activity was determined underconditions in which substrate hydrolysis increased linearly with timeand the change in fluorescence signal was proportional to theconcentration of free AMC.

Example B

Assay for Activity of α-Chymotrypsin

In 96-well microtiter plates bovine α-chymotrypsin, purchased from SigmaInc., was plated at 10 ng/mL (about 2 μM catalytic sites) in 0.5 M NaCl50 mM Hepes buffer. A fluorimetric substrate Suc-AAPF-AMC(succinyl-Ala-Ala-Pro-Phe-7-amido-4-methylcoumarin), purchased fromSigma Inc., St. Louis, Mo., USA was added to a final concentration of 25uM from a stock solution of 10 mM in dimethylsulfoxide. Reaction volumeswere 100 μl per well. After incubation for various periods of time atroom temperature, the concentration of free AMC was determined on aPerkin Elmer HTS 7000 Plus microplate reader, excitation 370 nM andemission 465 nM. α-Chymotrypsin activity was determined under conditionsin which substrate hydrolysis increased linearly with time and thechange in fluorescence signal was proportional to the concentration offree AMC.

Example C

Determination of IC₅₀ Values for HEP and α-Chymotrypsin Inhibitors

IC₅₀ values are typically defined as the concentration of a compoundnecessary to produce 50% inhibition of the enzyme's activity. IC₅₀values are useful indicators of the activity of a compound for itsdesignated use. The proteasome inhibitors of the invention can beconsidered active if they have IC₅₀ values of less than about 1micromolar for inhibition of human erythrocyte proteasome (HEP). In someembodiments, the inhibitors show some specificity for HEP and the ratioof the IC₅₀ for inhibition of bovine α-chymotrypsin versus the IC₅₀ forinhibition of HEP, i.e, IC₅₀ (α-Chymotripsin)/IC₅₀ (HEP), is greaterthen about 100.

Inhibition of the chymotrypsin-like activity of HEP and of bovineα-chymotrypsin was determined by incubating the enzyme with variousconcentrations of putative inhibitors for 15 minutes at 37° C. (or roomtemperature for α-chymotrypsin) prior to the addition of substrate. Eachexperimental condition was evaluated in triplicate, and replicateexperiments were performed for the inhibitors described herein.

Compounds of the present invention are considered active in the aboveidentified assay if their IC₅₀ values for inhibition of HEP are lessthan 1000 nanoMolar. Preferably compounds of the present invention willhave IC₅₀ values for inhibition of HEP less than 100 nanoMolar. Morepreferably compounds of the present invention will have IC₅₀ values forinhibition of HEP less than 10 nanoMolar. Compounds of the presentinvention have demonstrated, in the above identified assay, IC₅₀ valuesfor inhibition of HEP less than 1000 nanoMolar.

Example D

Cellular Assay for Chymotrypsin-like activity of Proteasome in Molt-4Cell Line

The chymotrypsin-like activity of proteasome in Molt-4 cells (humanleukemia) was assayed according to the following procedure. A briefdescription of the method was published previously (Harding et al., J.Immunol., 1995, 155, 1767).

Molt-4 cells were washed and resuspended in HEPES-buffered Saline (5.4mM KCl, 120 mM NaCl, 25 mM Glucose, 1.5 mM MgSO₄, 1 mM Na pyruvate, 20mM Hepes) and plated in 96-well microtiter white plates to a finalconcentration of 6×10⁶ cells/mL. Then various 5× proteasome inhibitorconcentrations (or diluted DMSO for controls), prepared from 250×DMSOsolutions by diluting 50-fold using HEPES-buffered saline, were added tothe plate to a final 1× concentration. After 15 minutes incubation at37° C., a fluorimetric cell permeable substrate (MeOSuc-FLF-AFC)(methoxysuccinyl-Phe-Leu-Phe-7-amido-4-trifluoromethylcoumarin)purchased from Enzyme Systems Products, catalogue number AFC-88, wasadded to each well at a final concentration of 25 μM from a stocksolution of 20 mM in DMSO. Reaction volumes were 100 μl per well.

The concentration of free AFC was monitored every 1.5 min for 30 min (22cycles) on a Polastar Optima, BMG Labtechnologies microplate reader,using an excitation wavelength of 390 nm and emission wavelength of 520nm. Proteasome activity was determined under conditions in whichsubstrate hydrolysis increased linearly with time and the change influorescent signal was proportional to the concentration of free AFC.

Example E

Determination of EC₅₀ Values for Proteasome Inhibitors in MOLT-4 CellLine

EC₅₀ values are typically defined as the concentration of a compoundrequired to produce an inhibition of the enzyme's activity halfwaybetween the minimum and the maximum response (0% and 85-90% respectivelyfor this assay). EC₅₀ values are useful indicators of the activity of acompound for its designated use. The compounds of the invention can beconsidered active if they have an EC₅₀ of less than about 10 micromolar.

Inhibition of chymotrypsin-like activity of proteasome in Molt-4 cellswas determined by incubating cells with various concentrations ofputative inhibitors for 15 minutes at 37° C. prior to the addition ofsubstrate. Each experimental condition was evaluated in triplicate, andreplicate experiments were performed for the inhibitors describedherein.

Compounds of the present invention are considered active in the aboveidentified assay if their EC₅₀ values for proteasome inhibition inMOLT-4 are less than 10 microMolar. Preferably compounds of the presentinvention will have EC₅₀ values for proteasome inhibition in MOLT-4 lessthan 2 microMolar. More preferably compounds of the present inventionwill have EC₅₀ values for proteasome inhibition in MOLT-4 less than 200nanomolar. Compounds of the present invention have demonstrated, in theabove identified assay, EC₅₀ values for proteasome inhibition in MOLT-4cells of less than 10 microMolar.

Example F

Assay for Trypsin-like Activity of the Proteasome

The trypsin-like activity of human proteasome can be assayed asdescribed above with the following modifications. Reactions can becarried out in Tris-glycerol buffer (pH 9.5) supplemented with 1 mM2-mercaptoethanol, and the substrate can be a fluorogenic substrate suchas benzyloxycarbonyl-Phe-Arg-AMC (100 μM).

After incubation for various periods of time at 37° C., theconcentration of free AMC can be determined on a Fluoroskan IIspectrofluorimeter with an excitation filter of 390 nm and an emissionfilter of 460 nm. Protease activity can be determined under conditionsin which substrate hydrolysis increases linearly with time and thechange in fluorescence is proportional to the concentration of free AMC.

Example G

In Vivo Inhibition of Cellular Muscle Breakdown

The effect of inhibitors on the unweighting atrophy of the soleus musclein juvenile rats can be determined by, for example, the proceduresdescribed in Tischler, Metabolism, 1990, 39, 756. For example, juvenilefemale Sprague-Dawley rats (80-90 g) can be tail-cast, hind limbsuspended as described in Jaspers, et al., J. Appl. Physiol., 1984, 57,1472. The animal's hind limbs can be elevated above the floor of thecage with each animal housed individually. Animals can have free accessto food and water, and can be weighed at the time of suspension and attime of termination. During the suspension period the animals can bechecked daily to ensure that their toes are not touching the floor ofthe cage, and that there is no swelling of the tail due to the cast.

Experimental Design—Part 1

Each experiment can begin with the suspension of 20 rats which arerandomly divided into 4 groups of 5 animals each. Group A can besuspended for 2 days, providing baseline data to approximate the soleusmuscle size in other animals suspended for longer times. Average bodyweights for the groups at the outset of the study can be compared andused as a correction factor for body size differences. Group B can be asecond control group which has the soleus of one limb treated with anaqueous solution of mersalyl after two days of unweighting, todemonstrate the ability to slow muscle atrophy during unweighting, foreach group of animals. At 2 days after unweighting commences, an aqueoussolution of mersalyl (200 nM; 4 μL/100 g initial body wt) can beinjected into one soleus. The contralateral muscle can be injected witha similar volume of 0.9% saline (“Vehicle”). The animals can bemaintained under Innovar-vet (10 μL/100 g body wt) tranquilizationduring the in situ injection procedure. After the injections, theanimals can be suspended for an additional 24 hours and the soleus canbe removed. Groups C and D for each experiment can be used for testingeach of two different embodiments of the disclosed compounds. Animalscan be treated as in group B, except that 1 mM proteasome inhibitor,contained in dimethysulfoxide (DMSO), can be injected into the soleus ofone leg and DMSO only into the contralateral soleus. Thus eachexperiment consists of two control groups and the testing of proteasomeinhibitors of the invention. The completion of five such experimentswith different pairs of inhibitors provides for an “n” value of 10 fortesting each inhibitor and each can be tested in two different shipmentsof animals.

Processing of the Soleus Muscle—Part 1

After the animal is sacrificed, the soleus can be excised, trimmed offat and connective tissue, and carefully weighed. The muscle can thenhomogenized in 10% trichloroacetic acid (TCA) and the precipitatedprotein pelleted by centrifugation. The pellet can then be washed oncewith 10% TCA and once with ethanol:ether (1:1). The final pellet can besolubilized in 4 ml of 1N sodium hydroxide. The sample can be thenanalyzed for protein content by the biuret procedure, using albumin as astandard.

Data Analysis—Part 1

The effect of inhibitors on total muscle protein content can be examinedprimarily by paired comparison with the untreated contralateral muscle.The ratio of contents can be calculated and then analyzed statisticallyby analysis of variance (“ANOVA”). The left leg can always be thetreated leg so that the protein content ratios can be compared to thenon-treated control animals as well. In this way, a significantdifference can be shown by comparing the protein content of the twolegs, as well as the relative effectiveness of the tested inhibitors. Apaired student test can also be performed for the effect of eachseparate treatment. The non-treated control data also provide anestimate of protein content of day 2. This allows approximation of theprotein changes over the 24 hours of treatment for each of the Groups B,C, and D.

Experimental Design—Part 2

Each experiment can consist of 10 animals with groups of 5 animals beingtested with one of the inhibitors for its effect on protein synthesis.Control animals are not needed for this aspect of the study as thecontralateral DMSO-treated muscle serves as the paired control for theinhibitor-treated muscle. Each group can be injected as described forgroups C and D in part 1. Twenty-four hours after the in situ treatmentthe fractional rate of protein synthesis can be analyzed in both soleusmuscles. Each muscle can be injected with a 0.9% saline solution (3.5μl/100 g final body wt) containing ³H-phenylalanine (50 mM; 1μCi/^(m)l). Fifteen minutes later the middle two-thirds of the musclecan be excised and the muscle can be processed as described below.

Processing of the Soleus Muscle—Part 2

The muscle can be first washed for 10 minutes in 0.84% saline containing0.5 mM cycloheximide, to terminate protein synthesis, and 20 mMcycloleucine, to trap phenylalanine in the cell. The muscle can then behomogenized in 2.5 mL of ice-cold 2% perchloric acid. The precipitatedprotein can be pelleted by centrifugation. One aliquot of thesupernatant can be taken for liquid scintillation counting and anotheraliquot can be processed for conversion of phenylalanine tophenethylamine to determine the soluble phenylalanine concentrationfluorometrically. See, e.g., Garlick, et al., Biochem. J., 1980, 192,719. These values can provide the intracellular specific activity. Thespecific activity of phenylalanine in the muscle protein can bedetermined after hydrolyzing the protein by heating in 6N HCl. The aminoacids released can be solubilized in buffer. One aliquot can be takenfor scintillation counting and another for analysis of phenylalanine asfor the supernatant fraction. The fractional rate of protein synthesiscan be calculated as: protein specific activity/intracellular specificactivity.times.time.

Data Analysis—Part 2

Analyses of protein synthesis can be on a paired basis for eachinhibitor. Student paired t test comparisons of the contralateralmuscles can determine whether there is any effect of the inhibitor onprotein synthesis. Protein breakdown can be calculated approximately asthe fractional rate of protein synthesis (from part 2) plus thefractional rate of protein accretion (from part 1), where protein lossyields a negative value for protein accretion.

Qualitatively the ability of inhibitors to slow protein loss withoutaffecting protein synthesis indicates a slowing of protein degradation.

Example H

In vivo Investigation of Anti-Tumor Activity

Materials

The proteasome inhibitors used for in vivo studies can be formulated inan appropriate medium for intravenous (iv) or oral (po) administration.For example, for the iv administration the compounds can be administereddissolved in 0.9% NaCl, or in mixtures of 0.9% NaCl, solutol HS15 anddimethylsulfoxide, for example in the ratio 87:10:3 (v:v:v),respectively.

Cell Lines

The following human and murine tumor cell lines of differenthistological origine can be used to test the antitumor activity of thecompounds of the invention: H460 (human, lung), A2780 (human, ovary),PC-3 (human, prostate), LoVo (human, colon), HCT116 (human, colon),BXPC3 (human, pancreatic), PANC-1 (human, pancreatic), MX-1 (human,mammary), MOLT (human, leukemia), multiple myeloma (human, myeloma), YC8(murine, lymphoma), L1210 (murine, leukemia), 3LL (murine, lung).

Animal Species

5-6 weeks immunocompetent or immunodeprived mice are purchased fromcommercial sources, for example from Harlan (Correzzana, Mi Italy). CD1nu/nu mice are maintained under sterile conditions; sterilized cages,bedding, food and acidified water are used.

Tumor Cell Implantation and Growth

Solid tumor models of different hystotype (lung, ovary, breast,prostate, pancreatic, colon) can be transplanted subcutaneously (sc.)into the axillary region of immunocompetent mice (murine models) or inimmunodeprived mice (human models). Human tumor cell lines, originallyobtained from ATCC, can be adapted to grow “in vivo” as solid tumor from“in vitro culture”.

Hematological human or murine tumor models can be transplanted intodifferent sites (iv, ip, is or sc) in immunocompetent mice (murinetumors) or in immunodeprived mice (human leukemia, lymphoma and myelomamodels), according to their highest tumor take.

Drug Treatment

Mice bearing solid (staged) or hematological tumors are randomized inexperimental groups (10 mice/group). For solid tumors, an average tumorweight of 80-100 mg for each group is considered to start the treatment;mice with the smallest and largest tumors are discarded.

Experimental groups are randomly assigned to the drug treatment and tothe control group. Animals can be treated iv or orally, depending on theoral bioavailability with the compounds following different treatmentschedules: iv weekly or twice weekly, or by daily oral administration.

On solid tumor models, drug treatment can begin when the tumor sizeranges between 80-100 mg after tumor transplantation (Day 0).

The compounds can be administered in a volume of 10 mL/Kg bodyweight/mouse in the appropriate solvent.

Parameters of Antitumor Activity

The following parameters can be assessed for the evaluation of theantitumor activity:

-   -   growth of primary solid tumor; in each mouse is monitored by        caliper measurement twice weekly;    -   survival time of treated mice as compared to control mice    -   twice weekly body weight evaluation of individual mice.

The tumor growth inhibition, TWI % (percentage of primary tumor growthinhibition in comparison with vehicle treated control groups) or theRelative tumor growth inhibition, RTWI % in case of staged tumors, isevaluated one week after the last drug treatment and the Tumor weight(TW) can be calculated as follows:TW=1/2ab²where a and b are long and short diameters of the tumor mass in mm.

The antitumor activity can be determined as tumor weight inhibition (TWI%), which is calculated according to the formula:

${{TWI}\mspace{14mu}\%} = {100 - {\frac{{mean}\mspace{14mu}{TW}\mspace{14mu}{treated}}{{mean}\mspace{14mu}{TW}\mspace{14mu}{controls}} \times 100}}$

The RTWI % (relative percentage of primary tumor growth inhibition incomparison with vehicle treated control groups) is evaluated one weekafter the last drug treatment, according to the following formula:

$\mspace{79mu}{{{RTWI}\mspace{14mu}\%} = {100 - {\frac{{mean}\mspace{14mu}{RV}\mspace{14mu}{of}\mspace{14mu}{treated}\mspace{14mu}{mice}}{{mean}\mspace{14mu}{RV}\mspace{14mu}{of}\mspace{14mu}{controls}\mspace{14mu}{mice}} \times 100}}}$${{where}\mspace{14mu}{RV}} = \frac{{Vt}\mspace{14mu}\left( {{tumor}\mspace{14mu}{weight}\mspace{14mu}{on}\mspace{14mu}{day}\mspace{14mu} t} \right)}{V_{O}\mspace{14mu}\left( {{initial}\mspace{14mu}{tumor}\mspace{14mu}{weight}\mspace{14mu}{at}\mspace{14mu}{the}\mspace{14mu}{outset}\mspace{14mu}{of}\mspace{14mu}{treatment}} \right)}$

The Percent of Tumor Regression can be calculated as regressions interms of relative tumor weight, determined as tumor weight at given daydivided by initial tumor weight at the outset the experiment.

On haematological tumour models the antitumor activity can be determinedas percentage increase of the median survival time of mice expressed asthe ratio (T/C %) of the median survival time of the treated group (T)to that of the control group (C). Animals which are tumour-free at theend of the experiment (60 days after transplantation) are excluded fromthe calculation and considered as long term survivors (LTS).

Evaluation of Toxicity in Tumor Bearing Mice

Toxicity can be evaluated daily on the basis of the gross autopsyfindings and the weight loss. Mice are considered to have died oftoxicity when death occurs before the death of vehicle treated controlanimals, or when significant body weight loss (>20%), and/or spleen andliver size reduction are observed.

The BWC % (Body weight change %) is assessed as follow: 100−(mean bodyweight of mice at given day/mean body weight at start of treatment)×100.This value is determined one week after the last treatment with the testcompound.

Example K

In Vitro Viability of Cells

The IC₅₀ values measuring in vitro viability of cells in the presence oftest compounds can be determined according to the following procedure.Cells can be seeded in 96-well plates at varying densities and thenassayed using the Calcein-AM viability assay after 24 hours to determinethe optimal final density for each cell type. Cells can then be seededin 96-well plates at the determined density in 100 μL of an appropriatecell media known to one skilled in the art.

Serial dilutions of test compounds can be made so that theconcentrations are twice the desired concentration to be evaluated. When100 μL of the dilution is then added to the cells plated in 100 μL ofmedia, a final concentration of, for example, 0, 11.7, 46.9, 187.5, 375,and 750 nM can be obtained. Compounds can be added to the plates threeto four hours after seeding the cells, then the plates can be incubatedat 37° C. for the desired time point (e.g., one, two, or three days).

Calcein-AM viability assays can be conducted at the desired time pointsas follows. Media can be aspirated using a manifold and metal plate toleave approximately 50 μL/well. The wells can be washed three times with200 μL DPBS, aspirating each time with the manifold to leave 50 μL/well.A 8 μM solution of Calcein-AM in DPBS can be prepared and 150 μL can beadded to each well. The plates can then be incubated at 37° C. for 30minutes. After incubation, calcein can be aspirated with the manifoldand cells can be washed with 200 μL DPBS as before. After finalaspiration, fluorescence can be measured using a Cytofluor 2300fluorescence plate reader. Negative controls can contain media and nocells, and experiments can be conducted in triplicate.

Example L

Kinetic Experiments In Vitro

Compounds of the invention can be tested for proteasome inhibitoryactivity using a protocol described in Rock, et al., Cell, 1994, 78,761. According to this procedure, dissociation constants (K_(i)) for theequilibrium established when proteasome and test compound interact toform a complex. The reactions can be carried out using SDS-activated 20Sproteasome from rabbit muscle, and the proteasome substrate can beSuc-LLVY-AMC.

Example M Inhibition of Activation of NF-κB

Compounds of the invention can be tested for inhibiting the activity ofNF-κB by carrying out the assay described in Palombella, et al., Cell,1994, 78, 773). For example, MG63 osteocarcinoma cells can be stimulatedby treatment with TNF-α for designated times. Whole cell extracts can beprepared and analyzed by electrophoretic mobility shift assays using thePRDII probe from the human IFN-β gene promoter.

Example N Compound Activity

Using the assays of Example C and Example E above the following TableF-1 demonstrates the utility of compounds of the invention forproteasome inhibition. In the following Tables, for the inhibition ofHEP, Example C, compounds of the present invention with a “+” are lessthan 1000 nM; compounds of the present invention with a “++” are lessthan 100 nM; and compounds of the present invention with a “+++” areless than 10 nM in IC₅₀ for HEP inhibition. In the following Tables, forthe inhibition of MOLT4, Example E, compounds of the present inventionwith a “+” are less than 10000 nM; compounds of the present inventionwith a “++” are less than 2000 nM; and compounds of the presentinvention with a “+++” are less than 200 nM in EC₅₀ for HEP inhibition.Where “>+” occurs activity was greater than the limits of the assay.Where no IC₅₀ value or EC₅₀ value is represented, data has yet to bedetermined.

TABLE F-1 Example # HEP (IC₅₀) MOLT4 (EC₅₀) D.1.1 +++ +++ D.1.2 ++ ++D.1.3 +++ ++ D.1.4 +++ +++ D.1.5 +++ ++ D.1.6 ++ ++ D.1.7 ++ + D.1.8 +++++ D.1.9 ++ D.1.10 ++ ++ D.1.11 ++ >+ D.1.12 +++ ++ D.1.13 +++ + D.1.14++ >+ D.2 +++ +++ D.2.1 +++ ++ D.2.2 +++ >+ D.2.3 +++ +++ D.2.4 +++ +++D.2.5 +++ ++ D.2.6 ++ + D.2.7 +++ +++ D.2.8 ++ +++ D.2.9 +++ +++ D.2.10+++ +++ D.3.1 +++ +++ D.3.2 +++ +++ D.3.3 +++ ++ D.3.7 +++ +++ D.3.8 ++++++ D.3.11 +++ +++ D.3.12 +++ +++ D.3.15 +++ +++ D.3.24 +++ +++ D.3.26+++ +++ D.3.27 +++ +++ D.3.29 +++ +++ D.3.31 ++ ++ D.3.32 +++ +++ D.3.34+++ +++ D.3.36 +++ +++ D.3.37 +++ +++ D.3.38 +++ +++ D.3.39 +++ +++D.3.43 +++ +++ D.3.49 +++ ++ D.3.50 +++ +++ D.3.54 +++ +++ D.3.55 ++++++ D.3.57 +++ +++ D.3.58 +++ +++ D.3.59 +++ ++ D.3.62 +++ +++ D.3.64+++ +++ D.3.66 +++ +++ D.3.67 +++ +++ D.3.68 +++ D.3.69 +++ D.3.70 ++++++ D.3.73 +++ +++ D.3.75 +++ +++ D.3.76 +++ D.3.77 +++ D.3.78 +++D.3.80 +++ D.3.87 +++ D.3.89 +++ D.3.91 +++ +++ D.3.92 +++ +++ D.3.93+++ +++ D.3.94 +++ +++ D.3.96 +++ +++ D.3.97 +++ +++ D.3.102 +++ ++D.3.103 +++ ++ D.3.104 +++ ++ D.3.105 +++ ++ D.3.115 +++ D.3.117 +++ +++D.3.119 +++ +++ D.3.122 +++ +++ D.3.124 +++ +++ D.3.125 +++ +++ D.3.126+++ +++ D.3.128 +++ ++ D.3.129 +++ +++ D.3.130 +++ D.3.131 +++ +++D.3.132 +++ +++ D.3.133 +++ ++ D.3.136 +++ >+ D.3.137 ++ + D.3.138 ++ ++D.3.161 +++ ++ D.3.174 ++ +++ D.3.175 ++ ++ D.3.176 +++ +++ D.3.177 ++++++ D.3.178 ++ +++ D.3.179 +++ +++ D.3.180 +++ +++ D.3.182 ++ ++ D.3.185+++ +++ D.3.186 +++ +++ D.3.189 +++ +++ D.3.190 +++ +++ D.3.191 +++ +++D.3.192 ++ + D.4.3 +++ +++ D.4.4 +++ +++ D.4.6 ++ +++ D.4.7 ++ +++ D.4.8++ +++ D.4.9 ++ +++ D.6.3 +++ +++ D.6.5 +++ +++ D.6.8 ++ +++ D.6.9 ++++++ D.7.1 +++ + D.7.2 +++ + D.7.3 +++ + D.7.4 +++ >+ D.7.5 +++ ++ D.7.6+++ >+ D.7.7 +++ >+ D.7.8 +++ >+ D.7.11 +++ + D.7.12 +++ >+ D.7.17 +++++ D.7.19 +++ + D.7.20 +++ + D.7.21 +++ + D.7.23 +++ >+ D.7.24 +++ ++D.7.25 +++ + D.7.26 +++ + D.7.27 +++ + D.7.28 +++ >+ D.7.30 ++ >+ D.7.31+++ >+ D.7.32 +++ + D.7.33 +++ + D.7.35 +++ >+ D.7.36 +++ + D.7.37+++ >+ D.7.38 +++ ++ D.7.39 +++ + D.7.41 +++ +++ D.7.60 +++ + D.7.61+++ >+ D.8 +++ +++ D.8.4 ++ +++ D.8.5 +++ +++ D.8.6 +++ +++ D.8.18 ++ ++D.8.19 +++ +++ D.8.20 +++ +++ D.9 +++ +++ D.12 +++ +++ D.16.6 +++ +++D.18 +++ +++ D.19 +++ +++ D.24.3 +++ +++ D.24.4 +++ +++ D.24.6 +++ +++D.24.8 +++ +++ D.24.9 +++ +++ D.24.10 +++ +++ D.24.11 +++ +++ D.24.12+++ +++ D.24.14 +++ +++ D.24.15 +++ +++ D.24.16 +++ +++ E.1.1 +++ >+E.1.2 +++ + E.1.3 +++ ++ E.1.4 +++ ++ E.1.5 +++ >+ E.1.6 ++ + E.1.7+++ + E.1.8 +++ >+ E.1.10 +++ E.1.11 +++ ++ E.1.12 +++ >+ E.1.13 +++ +E.1.14 +++ E.1.15 +++ ++ E.1.16 +++ +++ E.1.17 +++ +++ E.1.18 +++ +++E.1.19 +++ ++ E.1.20 +++ +++ E.1.21 +++ +++ E.1.22 +++ >+ E.1.23 +++ +++E.1.24 +++ +++ E.1.25 +++ +++ E.1.26 +++ +++ E.1.27 +++ +++ E.1.28 +++++ E.1.29 +++ ++ E.1.30 +++ + E.2.1 +++ +++ E.2.2 +++ ++ E.2.3 +++ +E.2.4 +++ >+ E.2.5 +++ + E.2.6 +++ ++ E.2.7 +++ + E.2.8 +++ + E.2.9 +++++ E.2.10 +++ >+ E.2.11 +++ >+ E.2.12 +++ +++ E.2.13 +++ + E.2.14 +++ >+E.2.15 +++ >+ E.2.16 +++ >+ E.2.18 +++ + E.2.19 +++ + E.2.20 +++ +E.2.21 +++ + E.2.22 +++ ++ E.2.23 +++ ++ E.2.24 +++ >+ E.2.25 +++ +E.2.26 +++ >+ E.2.27 +++ >+ E.2.28 +++ >+ E.2.29 +++ + E.2.31 +++ >+E.2.32 +++ >+ E.2.33 +++ + E.2.34 +++ + E.2.35 +++ >+ E.2.36 +++ >+E.2.37 +++ >+ E.2.38 +++ + E.2.39 +++ ++ E.2.40 +++ + E.2.41 +++ >+E.2.42 +++ >+ E.2.45 +++ +++ E.2.46 +++ ++ E.2.47 +++ >+ E.2.48 +++ ++E.2.49 +++ >+ E.2.50 +++ >+ E.2.51 ++ >+ E.2.52 +++ + E.2.53 ++ >+E.2.54 +++ >+ E.2.55 +++ + E.2.56 +++ + E.2.57 +++ + E.2.58 +++ + E.2.59+++ + E.2.60 +++ + E.2.61 +++ + E.2.62 +++ >+ E.2.64 +++ >+ E.2.65 ++ >+E.2.66 +++ >+ E.2.67 +++ + E.2.68 +++ >+ E.2.69 +++ >+ E.2.70 +++ >+E.2.75 +++ >+ E.2.76 +++ + E.2.77 +++ + E.2.78 +++ + E.2.79 +++ ++E.2.80 ++ + E.2.81 ++ + E.3 +++ +++ E.3.1 +++ +++ E.3.2 +++ +++ E.3.3+++ +++ E.3.4 ++ +++ E.3.5 +++ +++ E.3.6 +++ +++ E.3.7 +++ +++ E.3.8 ++++++ E.3.9 +++ +++ E.3.10 +++ +++ E.4 +++ +++ E.4.1 ++ ++ E.4.2 ++ +++E.4.3 +++ +++ E.5 +++ +++ E.5.1 +++ +++ E.5.2 +++ +++ E.5.3 ++ ++ E.5.5+++ +++ E.5.6 +++ +++ E.5.7 +++ +++ E.5.8 +++ +++ E.5.9 +++ +++ E.5.10+++ +++ E.5.11 +++ +++ E.5.12 +++ +++ E.5.13 +++ +++ E.5.16 +++ +++E.5.17 +++ ++ E.5.18 +++ +++ E.5.19 +++ +++ E.5.20 +++ +++ E.5.21 ++++++ E.5.22 +++ +++ E.5.24 +++ ++ E.5.25 +++ +++ E.5.26 +++ ++ E.5.27 ++++++ E.5.28 +++ +++ E.5.29 +++ +++ E.5.30 +++ ++ E.5.31 +++ +++ E.5.32+++ +++ E.5.33 +++ ++ E.5.34 +++ +++ E.5.35 +++ +++ E.5.36 ++ ++ E.5.37+++ +++ E.5.40 +++ +++ E.5.41 ++ +++ F.1 +++ F.2.1 ++ ++Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, the compounds of Formula (I) can beadministered in the form of pharmaceutical compositions. Thesecompositions can be administered by a variety of routes including oral,rectal, transdermal, subcutaneous, intravenous, intramuscular, andintranasal, and can be prepared in a manner well known in thepharmaceutical art.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, one or more of the compounds of Formula (I)above in combination with one or more pharmaceutically acceptablecarriers. In making the compositions of the invention, the activeingredient is typically mixed with an excipient, diluted by an excipientor enclosed within such a carrier in the form of, for example, acapsule, sachet, paper, or other container. When the excipient serves asa diluent, it can be a solid, semi-solid, or liquid material, which actsas a vehicle, carrier or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing, forexample, up to 10% by weight of the active compound, soft and hardgelatin capsules, suppositories, sterile injectable solutions, andsterile packaged powders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 100 mg, more usually about 10 to about30 mg, of the active ingredient. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, 0.1 to about 500 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions in can be nebulized by use of inert gases. Nebulizedsolutions may be breathed directly from the nebulizing device or thenebulizing device can be attached to a face masks tent, or intermittentpositive pressure breathing machine. Solution, suspension, or powdercompositions can be administered orally or nasally from devices whichdeliver the formulation in an appropriate manner.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications. Anamount adequate to accomplish this is referred to as “therapeuticallyeffective amount.” Effective doses will depend on the disease conditionbeing treated as well as by the judgement of the attending cliniciandepending upon factors such as the severity of the disease, the age,weight and general condition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of the compounds of the present invention canvary according to, for example, the particular use for which thetreatment is made, the manner of administration of the compound, thehealth and condition of the patient, and the judgment of the prescribingphysician. The proportion or concentration of a compound of theinvention in a pharmaceutical composition can vary depending upon anumber of factors including dosage, chemical characteristics (e.g.,hydrophobicity), and the route of administration. For example, thecompounds of the invention can be provided in an aqueous physiologicalbuffer solution containing about 0.1 to about 10% w/v of the compoundfor parenteral administration. Some typical dose ranges are from about 1μg/kg to about 1 g/kg of body weight per day. In some embodiments, thedose range is from about 0.01 mg/kg to about 100 mg/kg of body weightper day. The dosage is likely to depend on such variables as the typeand extent of progression of the disease or disorder, the overall healthstatus of the particular patient, the relative biological efficacy ofthe compound selected, formulation of the excipient, and its route ofadministration. Effective doses can be extrapolated from dose-responsecurves derived from in vitro or animal model test systems.

The present invention also includes pharmaceutical kits useful, forexample, in the treatment or prevention of inflammatory diseases, whichcomprise one or more containers containing a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of Formula(I). Such kits can further include, if desired, one or more of variousconventional pharmaceutical kit components, such as, for example,containers with one or more pharmaceutically acceptable carriers,additional containers, etc., as will be readily apparent to thoseskilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference cited in the presentapplication, including patents, published patent applications, andjournal articles, is incorporated herein by reference in its entirety.

What is claimed is:
 1. A compound having Formula (I):

or a pharmaceutically acceptable salt, stereoisomeric or tautomeric form thereof, wherein: R¹ is C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, or C₃-C₇ cycloalkyl; R² is H; Q is —B(OH)₂, —B(OR¹⁴)₂, or a cyclic boronic ester wherein said cyclic boronic ester contains from 2 to 20 carbon atoms, and, optionally, a heteroatom which can be N, S, or O; R¹⁴ is H, C₁-C₄ alkyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl; X is R^(A)C(═O)—; R^(A)NHC(═O)—, R^(A)S(O)₂—, R^(A)SC(═O)—, or R^(A); R^(A) is C₁-C₂₀ alkyl optionally substituted with R²⁰; C₂-C₂₀ alkenyl optionally substituted with R²⁰; C₂-C₂₀ alkynyl optionally substituted with R²⁰; carbocyclyl optionally substituted with 1-5 R²²; or heterocarbocyclyl optionally substituted with 1-5 R²²; R²⁰ is selected from the group consisting of: —OR^(20a), —SR^(20a), —S(═O)R^(20a), —S(═O)₂R^(20a), —S(═O)₂—NHR^(20a), —SC(═O)R^(20a), —C(═O)R^(20a), —C(═O)NHR^(20a), —C(═O)O—R^(20a), phthalimido, —(O-alkyl)_(r), —O-alkyl-OH, —(O-alkyl)_(r)—OH, —OR^(20c), —SR^(20c), —O-alkyl-R^(20c), —S- alkyl-R^(20c), —S(═O)—R^(20c), —S(═O)₂—R^(20c), —S(═O)₂—NHR^(20c), —SC(═O)R^(20c), —C(═O)R^(20c), —C(═O)OR^(20c), —C(═O)NHR^(20c), carbocyclyl optionally substituted with 1-5 R²²; and heterocarbocyclyl optionally substituted with 1-5 R²²; R^(20a) is C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, or C₂-C₂₀ alkynyl; wherein said alkyl, alkenyl, or alkynyl is optionally substituted by one or more halo, C₁-C₄ alkyl, aryl, heteroaryl or —NHR^(20b); R^(20c) is carbocyclyl optionally substituted with 1-5 R²²; or heterocarbocyclyl optionally substituted with 1-5 R²²; R²² is selected from the group consisting of: C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, phenyl, halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino, dialkylamino, carboxyl, alkyl-OC(═O)—, alkyl-C(═O)—, aryl-OC(═O)—, alkyl-OC(═O)NH—, aryl-OC(═O)NH—, alkyl-C(═O)NH—, alkyl-C(═O)O—, (alkyl-O)_(r)-alkyl, HO-(alkyl-O)_(r)-alkyl-, —OH, —SH, —CN, —N₃, —CNO, —CNS, alkyl-S(═O)—, alkyl-S(═O)₂—, H₂NS(═O)—, and H₂NS(═O)₂—; and r is 2, 3, 4, 5, 6, 7, 8, 9, or
 10. 2. The compound of claim 1 wherein X is R^(A)C(═O)—.
 3. The compound of claim 1 wherein X is R^(A)C(═O)—and R^(A) is aryl optionally substituted with 1-3 substituents selected from the group consisting of C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino, dialkylamino, alkyl-OC(═O)—, alkyl-C(═O)—, alkyl-OC(═O)NH—, alkyl-C(═O)NH—, —OH, —CN, alkyl-S(═O)—, and alkyl-S(═O)₂. 